β-catenin  of the canonical  Wnt signalling pathway  plays a role in cell fate determination, as it is critical for osteoblastogenesis, and the differentiation of chondrocytes into osteoblasts. Knock out of the entire pathway results in early  embryonic death , therefore most research of this nature utilised conditional knockouts of the pathway. [ 2 ]


During mandible development, most of it is formed through intramembranous ossification, where  endochondral ossification  will occur in the proximal region.
TGF-β is important for cell proliferation and differentiation during skeletogenesis. During this process, TGF-β can stimulate differentiation into either chondrocytes or osteoblasts via  FGF ,  Msx1 , and  Ctgf  signalling pathways.
General gene  knock out  of the TGF-β resulted in death.  Conditional inactivation  of TGF-βr2 of osteochondroprogenitor cells in the  cranial neural crest  resulted in faster osteoprogenitor differentiation and disorganised chondrogenesis. [ 6 ]


TGF-β determines and regulates cell lineages during endochondral ossification through Sox9 and Runx2 signalling pathways. TGF-β will act as a stimulator of chondrogenesis, and an inhibitor of osteoblastic differentiation, by blocking the Runx2 factor through  Smad3  activation. Sox9 stimulates differentiation into chondrocytes. Sox9 blocked osteochondroprogenitor cells were found to express osteoblast marker genes, reprogramming the cells into the osteoblastic lineage. [ 6 ]
 [ 7 ]


Loss of TGF-β signalling will lead to reduced Sox9 activity, but not prevent it completely, suggesting that there must be other factors and signalling pathways regulating Sox9 activity. Once Sox9 activity is lost, differentiation into the osteoblastic lineage dominates. [ 8 ]


It is thought that through a combination of biochemical and biophysical stimuli, the uncommitted stem cells of the embryo will undergo differentiation into certain cell lineages. However the exact mechanism and signalling pathways are still unclear. Studies have shown that embryonic stem cells are more mechanosensitive than their differentiated counterparts.
During embryonic development mesenchymal cells will form cellular structures known as 'condensations.' These cellular units will then develop into skeletal and other tissues, such as cartilage, tendon, ligament and muscle tissue. [ citation needed ]


Osteoprogenitor cell condensations can aggregate, dissipate or condense depending on the signals present, however these still remain largely unknown. Depending on the different effects, the cellular condensations may differentiate into osteogenic or chondrocytic condensations. [ citation needed ]


The positioning of the osteoprogenitor cell condensations determines the cell lineage before the signalling molecules can. This is due to their positions relative to any epithelial surfaces. Osteoblastic and chondrogenic condensations differ in their biophysical parameters within the embryo. Their distance in relation to the nearest epithelial surface will determine the cell lineage. For example, osteoblastic condensations are closer to epithelial surfaces so they will be exposed to more biophysical and biochemical stimuli due to the proximity and increased cell-epithelial interactions. [ 2 ] [ 9 ] [ 10 ]


The regeneration potential of skeletal progenitor cells declines with age. [ 11 ]  This reduction of regeneration potential is associated with increased risk of  bone fractures  with age. Central to reduction of regeneration potential are the skeletal  stem progenitor cells  since they are responsible for the growth, regeneration and repair of bone tissue. [ 11 ]  With increasing age the functionality of adult stem cells declines as  DNA damages  and  mutations  accumulate. [ 12 ]


Deletion of the Trsp gene in osteochondroprogenitor cells results in abnormal bone growth, delayed ossification, chondronecrosis and dwarfism. General Trsp gene deletion is lethal to the embryo. The results of this research was used as a model for  Kashin-Beck disease . Kashin-Beck is a result of combinatorial environmentally induced by factors such as: toxic mould, contaminated grains by mycotoxins, and mostly by  selenium deficiency , which is necessary for  selenoprotein  function. The disease has symptoms similar to those resulting from Trsp gene knockout. [ 13 ]


Loss of the regulator,  Pten , of the  Phophatidylinositol3' kinase  pathway results in skeletal overgrowth and  growth plate  dysfunction, due to overproduction of the matrix and accelerated hypertrophic differentiation. [ 14 ]


Ostravik-Lindemann-Solberg syndrome , also known as  heart defect-tongue hamartoma-polysyndactyly syndrome  is a rare, multi-systemic  genetic disorder  which is characterized by  congenital heart defects ,  tongue   hamartomas , postaxial  polydactyly  of the hand, and  syndactylism  of the foot. This condition is thought to be caused by an autosomal dominant mutation in the  WDPCP  gene, in  chromosome 2 . [ 1 ] [ 2 ]  Only 5 cases have been recorded in medical literature. [ 3 ]


A  palatal obturator  is a  prosthesis  that totally occludes an opening such as an oronasal  fistula  (in the  roof of the mouth ). They are similar to  dental retainers , but without the front wire. Palatal obturators are typically short-term prosthetics used to close defects of the hard/soft palate that may affect speech production or cause  nasal regurgitation  during feeding. Following surgery, there may remain a residual orinasal opening on the palate, alveolar ridge, or  vestibule of the larynx . A palatal obturator may be used to compensate for hypernasality and to aid in speech therapy targeting correction of compensatory articulation caused by the cleft palate.  In simpler terms, a palatal obturator covers any fistulas (or "holes") in the roof of the mouth that lead to the nasal cavity, providing the wearer with a plastic/acrylic, removable roof of the mouth, which aids in speech, eating, and proper air flow.


Palatal obturators are not to be confused with  palatal lifts  or other prosthetic devices. A palatal obturator may be used in cases of a deficiency in tissue, when a remaining opening in the palate occurs. In some cases it may be downsized gradually so that tissue can strengthen over time and compensate for the decreasing size of the obturator. The palatal lift however, is used when there is not enough palatal movement. It raises the palate and reduces the range of movement necessary to provide adequate closure to separate the nasal cavity from the oral cavity.  Speech bulbs  and palatal lifts aid in  velopharyngeal closure  and do not obturate a fistula. A speech bulb, yet another type of prosthetic device often confused with a palatal obturator, contains a pharyngeal section, which goes behind the soft palate.


Palatal obturators are needed by individuals with  cleft palate , those who have had tumors removed or have had traumatic injuries to their palate.


A  palatal plate  is a  prosthetic device , generally consisting of an acrylic plate and retention clasps of orthodontic wire, which covers a fistula of the palate. It may be used to aid in improving  articulation  and feeding. The blockage of the opening helps improve  hypernasality  and suckling ability for babies. In the case of a labial-oral-nasal  fistula , the plate may include an anterior upward extension to fully occlude the passageway running between the labial surface of the  alveolus , alveolus, and nasal cavity. The plate may be constructed to include any  congenitally  missing teeth to improve articulation and appearance. Individuals who use palatal plates must be monitored periodically by their dental professionals due to possible tissue irritation by the plate. Materials such as food particles, oral mucosa and  secretions  may cause buildup on the upper surface of the plate; therefore, it is essential to clean a palatal obturator at least twice a day to avoid tissue irritation. There are also more specific terms used for obturators depending on their time and purpose of use: Photo Examples of the Latham Device or the Nasal Alveolar are prime examples for use in Cleft Palate Deformities.


Palatal adhesives  are oral adhesives or skin barrier materials used to occlude a fistula of the hard palate. Obturators of this type must be removed before eating and drinking. Users must cut the new piece of adhesive and hold it over the fistula until it adheres. Adhesives are not to be used for soft palate fistulae if the soft palate has some mobility due to possible unintentional dislodging and digestion of the material.


This fixed obturator is based on the Nance appliance, which was originally used as a space maintainer in dentistry and orthodontics, but has been redesigned for closing anterior palatal fistulas in patients with cleft lip and palate. The Nance obturator may be used when the surgical closure of the fistula is not feasible and a removable device is not successful.


Often a palatal obturator is used because a palatal fistula can affect development and proper articulation. As fistula sizes vary, small fistulae tend to result in little to no speech alterations whereas large fistulae tend to result in audible nasal emissions and weak pressure with and/or without  hypernasality .  Misarticulations , abnormal nasal resonance and nasal escape or air often results from the problem. Fistulae may decrease intraoral air pressure during production of oral pressure consonants causing distortion of sounds as well as increase in nasal airflow. It is common for an individual with a fistula to compensate for a loss of pressure during speech sound production by attempting to regulate intraoral air pressure with increasing respiration effort and using compensatory articulation. Middorsum palatal stops (atypical place of articulation) often results from palatal fistulae causing sound distortions during speech. Occlusion for the fistula is attempted by speakers with deviant tongue placements during these palatal stops.


The palatal obturation may be managed temporarily or may be sustained for longer periods of time. Location-specific palatal obturation has been documented to significantly improve articulation errors, hypernasality (based on listener judgments), and nasal emissions (immediately post-obturation only). Usage of more anterior tongue placements is considered a primary target for speech therapy. The relationship between palatal openings and articulation is important to note prior to surgical plans to ascertain timing of speech therapy and most appropriate therapy goals and approach. Speech therapy may be most beneficial prior to sustained palatal obturation rather than short-term obturation.


A  papillary fibroelastoma  is a  primary tumor of the heart  that typically involves one of the  heart valves . [ 1 ]  Papillary fibroelastomas, while considered uncommon, make up about 10 percent of all primary tumors of the heart. [ 2 ]  They are the third most common type of primary tumor of the heart, [ 3 ]  behind  cardiac myxomas  and cardiac  lipomas .


A papillary fibroelastoma is generally considered pathologically benign, [ 4 ]  however outflow obstruction or embolism can be associated with  syncope , [ 5 ]   chest pain ,  heart attack ,  stroke [ 6 ] [ 7 ]  and  sudden cardiac death .


Symptoms due to papillary fibroelastomas are generally due to either mechanical effects of the tumor or due to embolization of a portion of the tumor to a distal organ. In particular, chest pain or syncope may be due to transient occlusion of the  left main coronary artery  by the tumor, [ 8 ]  while a heart attack or sudden cardiac death may be due to embolization of a portion of the tumor into a coronary artery. [ 9 ]


Papillary fibroelastoma are typically found and accurately diagnosed by  imaging . The  diagnosis  is confirmed by  pathology .  Histologically , papillary fibroelastomas have branching  avascular   papillae , composed of  collagen , that are covered by  endothelium . [ citation needed ]


If the tumor is found incidentally in an asymptomatic person, the treatment approach is controversial. Certainly a conservative approach is warranted in certain individuals. [ 10 ]  If the tumor is large, greater than 1 cm in asymptomatic patients, [ 11 ]  and pedunculated, a case may be made for surgical excision prior to symptoms developing due to the higher risk of embolism. However, this is still considered controversial. [ 12 ]


If the papillary fibroelastoma is associated with symptoms, surgical excision is generally recommended for relief of symptoms. [ 10 ]  A minimally invasive approach may be possible if the tumor involves the  aortic valve [ 13 ]  or right atrium. [ 14 ]  In the case of aortic valve involvement, excision of the tumor is often valve-sparing, meaning that replacement of the valve with a  prosthetic valve  is not necessary. Repair of the native valve with a pericardial patch has been described. [ 15 ]


A  parasitic twin , also known as an  asymmetrical twin  or  unequal conjoined twin , occurs when a  twin   embryo  begins developing  in utero , but the pair does not fully separate, and one embryo maintains dominant development at the expense of the other. It results from the same processes that also produces  vanishing twins  and  conjoined twins , and may represent a continuum between the two. In parasitic twins, one ceases development during  gestation  and is  vestigial  to a mostly fully formed, otherwise healthy individual twin. The undeveloped twin is termed as  parasitic , because it is incompletely formed or wholly dependent on the body functions of the complete fetus. [ 1 ]  The independent twin is called the  autosite . The autosite, together with the parasite, are collectively referred to as  heteropagus twins . [ 2 ]


The  twin reversed arterial perfusion , or T.R.A.P. sequence, results in an 'acardiac twin', a parasitic twin that fails to develop a head, arms and a  heart . The parasitic twin, little more than a  torso  with or without legs, receives its blood supply from the host twin by means of an umbilical cord-like structure, much like a fetus  in fetu , except the acardiac twin is outside the autosite's body. The blood received by the parasitic twin has already been used by the normal fetus, and as such is already de-oxygenated, leaving little developmental nutrients for the acardiac twin. Because it is pumping blood for both itself and its acardiac twin, this causes extreme stress on the normal fetus' heart. Many T.R.A.P. pregnancies result in heart failure for the healthy twin. This twinning condition usually occurs very early in pregnancy. [ 3 ]  A rare variant of the acardiac fetus is the  acardius acormus  where the head is well developed but the heart and the rest of the body are rudimentary. While it is thought that the classical T.R.A.P./Acardius sequence is due to a retrograde flow from the umbilical arteries of the pump twin to the iliac arteries of the acardiac twin resulting in preferential caudal perfusion,  acardius acormus  is thought to be a result of an early embryopathy. [ 4 ]


Conjoined parasitic twins joined at the head are described as  craniopagus  or  cephalopagus , and  occipitalis  if joined in the  occipital  region or  parietalis  if joined in the  parietal  region.


Craniopagus parasiticus  is a general term for a parasitic head attached to the head of a more fully developed fetus or infant. [ 5 ]


Fetus  in fetu  sometimes is interpreted as a special case of parasitic twin, but may be a distinct entity.


Parastremmatic dwarfism  is a rare  bone disease  that features severe  dwarfism , thoracic  kyphosis  (a type of  scoliosis  that affects the upper back), a distortion and twisting of the limbs,  contractures  of the large joints, malformations of the  vertebrae  and  pelvis , and  incontinence . The disease was first reported in 1970 by Leonard Langer and associates; they used the term  parastremmatic  from the Greek  parastremma , or  distorted limbs , to describe it. On  X-rays , the disease is distinguished by a "flocky" or lace-like appearance to the bones. [ 2 ]  The disease is  congenital , which means it is apparent at birth. It is caused by a  mutation  in the  TRPV4  gene, located on  chromosome 12  in humans. The disease is inherited in an  autosomal   dominant  manner. [ 2 ] [ 3 ] [ 4 ]


Parastremmatic dwarfism is apparent at birth, with affected infants usually being described as "stiff", or as "twisted dwarfs" when the skeletal deformities and appearance of dwarfism further present themselves. Skeletal deformities usually develop in the sixth to twelfth month of an infant's life. The deformities may be attributed to  osteomalacia , a lack of  bone mineralization . [ citation needed ]


Parastremmatic Dwarfism is further characterised by short stature, bowing of extremeties and further neuroskeletal dysplasia. [ citation needed ]


Parastremmatic dwarfism is caused by a  missense mutation  (where one  amino acid  is replaced by another in a  gene sequence ) in the  TRPV4  gene, [ 4 ]   located  on the long arm of human  chromosome   12 , at 12q24.11. [ 5 ]  The mutation is in  exon  11 of the gene, and is labelled R594H; this means that the  codon  (the code for an amino acid molecule) for  arginine  was erroneously substituted by a codon for  histidine  at position 594 in that exon. This same mutation in the  TRVP4  gene is known to cause the  Kozlowski type  of  spondylometaphyseal dysplasia . [ 4 ] [ 6 ]


Parastremmatic dwarfism is inherited in an autosomal dominant manner, [ 7 ]  which means that the defective gene responsible for the disease is located on an  autosome  (chromosome 12 is an autosome), and one copy of the defective gene is sufficient to cause the disorder when inherited from a parent who also has the disorder. [ 2 ]


Parastremmatic Dwarfism results from mutations within the N-ankyrin domain of TRPV4, which has been identified to be involved in regulation of the TRPV4 calcium ion channel. This influx of calcium may be responsible for neuronal cell death, as well as affecting levels of circulating growth hormones. [ citation needed ]


Parastremmatic Dwarfism is a very rare disorder, and as of 2011, only 5 people were diagnosed worldwide. As such, functional analysis has proved elusive at this time. [ citation needed ]


Patterson syndrome , also called  pseudoleprechaunism , is an extremely rare syndrome, first mistaken as  Donohue syndrome  (also known as  leprechaunism ). [ citation needed ]


It is named for Dr. Joseph Hanan Patterson. [ 1 ]  It was described by Patterson and Watkins in 1962. [ 2 ]  The pathogenesis and cause of the Patterson syndrome was unknown until 1981. [ 3 ]


Patterson syndrome is characterized by the patient's having an unusual facial look, similar to that caused by leprechaunism. It primarily affects the connective tissue and the neuroendocrine system, giving rise to bronzed hyperpigmentation,  cutis laxa  of the hands and feet, bodily disproportion,  intellectual disability , and major bony deformities.   Radiographs  reveal a characteristic generalised skeletal  dysplasia . [ citation needed ]


It comprises  endocrine  abnormality,  hyperadrenocorticism ,  cushingoid  features, and  diabetes mellitus . One other case has shown premature  adrenarche . [ citation needed ]


A  pelvic digit ,  pelvic finger , or  pelvic rib  is a rare  congenital abnormality  in humans, in which  bone tissue  develops in the  soft tissue  near the  pelvis , resembling a  rib  or  finger  and often divided into one or more segments with  pseudo-articulations . Pelvic digits are typically  benign  and asymptomatic, and are usually discovered accidentally. Approximately 41 cases have been reported. [ 1 ]


The pelvic digit was first reported by D. Sullivan and W.S. Cornwell in 1974. [ 2 ]  Pelvic digits may be located at any level of the pelvis, the lower ribs, or even the anterior abdominal wall. It is theorized that pelvic digit anomalies arise during the  mesenchymal  stage of bone growth, within the first six weeks of  embryogenesis . Their formation may result from a failure of the  primordium  of the  coccyx  to fuse to the  vertebral column , leading to the independent development of a proto-rib structure. [ 1 ]


A  persistent cloaca  is a symptom of a complex  anorectal   congenital disorder , in which the  rectum ,  vagina , and  urinary tract  meet and fuse, creating a  cloaca , a single common channel. [ 1 ]


Cloacas appear in a wide spectrum of variation in females born with the malformation. The severity of the condition depends on where the three tracts have joined together. [ 2 ]  The single orifice, called a common channel, may occur varying in length from 1 to 10 cm. [ 3 ] [ 4 ]  The length of the common channel can be used to judge prognostic outcomes and technical challenges during surgical repair. A common channel less than 3 cm in length usually has good sphincter muscles and a well-developed  sacrum . [ 5 ]  This type of malformation happens when the embryonic anorectal and urogenital channels fail to separate during the sixth and seventh weeks of gestational development. Cloacal malformations are rare; they only occur in approximately 1 in 50,000 live births. [ 2 ]


Diagnosis of a female with a cloaca should be suspected in a female born with an  imperforate anus  and small looking genitalia. The diagnosis can be made clinically with tests like ultrasound, X-rays, voiding cystourethrogram (VCUG) and cloacagram. MRI of the spine and pelvis and endoscopic examinations may also be performed. [ 6 ]  Failure to identify a cloaca as being present in a newborn may be dangerous, as more than 90% have associated urological problems. The goal for treatment of a female born with cloaca is to achieve bowel control, urinary control, and sexual function, which includes  menstruation ,  sexual intercourse , and possibly  pregnancy . Cloacas probably occur in 1 in 20,000 live births. [ 7 ] [ 8 ]


Due to their complexity, cloacal malformations require multidisciplinary treatment from pediatric surgeons, urologists and gynecologists. Children diagnosed with this condition may also have anomalies in other organ systems and will likely require several different types of reconstructive surgeries. Depending on the severity of their condition, treatment may involve urinary, vaginal and colorectal reconstruction. [ 9 ]


The prognostic outcomes for this type of cloaca are good for bowel control and urinary function.  The surgical repair for this type of cloaca can usually be done by performing posterior sagittal approach without opening of the abdomen. A common channel longer than 3 cm in length usually has poor sphincter muscles and a poor sacrum, suggesting a prognostic outcome for bowel control and urinary function to be less likely. Common channels longer than 3 cm are generally considered more complex and more technically challenging in surgical repair. [ 7 ]


Pfeiffer syndrome  is a rare  genetic disorder , characterized by the premature fusion of certain bones of the  skull  ( craniosynostosis ), which affects the shape of the head and face. The syndrome includes abnormalities of the hands and feet, such as wide and deviated thumbs and big toes.


Pfeiffer syndrome is caused by mutations in the  fibroblast growth factor receptors   FGFR1  and  FGFR2 . The syndrome is grouped into three types: type 1 (classic Pfeiffer syndrome) is milder and caused by mutations in either gene; types 2 and 3 are more severe, often leading to death in infancy, caused by mutations in  FGFR2 . [ 2 ]


There is no cure for the syndrome. Treatment is supportive and often involves surgery in the earliest years of life to correct skull deformities and respiratory function. [ 2 ]  Most persons with Pfeiffer syndrome type 1 have a normal intelligence and life span; types 2 and 3 typically cause  neurodevelopmental disorders  and early death. Later in life, surgery can help in bone formation and facial construction.


Pfeiffer syndrome affects about 1 in 100,000 persons. [ 1 ]  The syndrome is named after a German geneticist,  Rudolf Arthur Pfeiffer  (1931–2012), who described it in 1964. [ 3 ]


Many of the facial characteristics result from the premature fusion of the skull bones ( craniosynostosis ). The head is unable to grow normally, which leads to a high, prominent forehead ( turri   brachycephaly ) and eyes that appear to bulge ( proptosis ) and are set wide ( hypertelorism ). In addition, there is an underdeveloped upper jaw ( maxillary hypoplasia ). More than half of children with Pfeiffer syndrome have hearing loss; dental problems are common. [ 4 ]  A baby with Pfeiffer syndrome may have a small, beak-shaped nose; crowded, crooked teeth; and sleep apnea, due to nasal blockage. There are three main types of Pfeiffer syndrome: type I is the mildest and most common; type II is the most severe, with neurological problems and a cloverleaf deformity; and type III is similar to type II, but without the cloverleaf deformity. [ 5 ]


In people with Pfeiffer syndrome, the thumbs and first (big) toes are wide and bend away from the other digits ( pollex varus  and  hallux varus ). Unusually short fingers and toes ( brachydactyly ) are also common, and there may be some webbing or fusion between the digits ( syndactyly ). [ 6 ]


Pfeiffer syndrome is strongly associated with mutations of the  fibroblast growth factor receptor 1  ( FGFR1 ) on  chromosome 8  or the  fibroblast growth factor receptor 2  ( FGFR2 ) gene on  chromosome 10 . [ 1 ] [ 7 ] [ 8 ] [ 9 ]  These genes code for  fibroblast growth factor receptors , which are important for normal bone development. [ 10 ]   Advanced paternal age  is thought to be a risk factor for sporadic cases of Pfeiffer syndrome due to an increase in mutations in sperm as men become older. [ 1 ] [ 11 ]


The most widely accepted clinical classification of Pfeiffer syndrome was published by  M. Michael Cohen  in 1993. [ 1 ] [ 12 ]  Cohen divided the syndrome into three possibly overlapping types, all of which are characterized by broad thumbs, broad great toes,  brachydactyly  and possibly  syndactyly : [ 13 ]


The key problem is the early fusion of the skull, which can be corrected by a series of surgical procedures, often within the first three months after birth. Later surgeries are necessary to correct respiratory and facial deformities. [ 2 ]


Children with Pfeiffer syndrome types 2 and 3 "have a higher risk for  neurodevelopmental disorders  and a reduced life expectancy" than children with Pfeiffer syndrome type 1, but if treated, favorable outcomes are possible. [ 14 ]  In severe cases, respiratory and neurological complications often lead to early death.


The syndrome is named after German geneticist  Rudolf Arthur Pfeiffer  (1931–2012). [ 15 ]  In 1964, Pfeiffer described eight individuals in three generations of a family who had abnormalities of the head, hands and feet ( acrocephalosyndactylia ) that were inherited in an  autosomal dominant  pattern. [ 1 ] [ 13 ] [ 3 ]


Phosphate diabetes  is a rare,  congenital ,  hereditary  disorder associated with inadequate  tubular reabsorption  that affects the way the body processes and absorbs  phosphate . [ 1 ]  Also named as X-linked dominant hypophosphatemic rickets ( XLH ), [ 2 ]  this disease is caused by a mutation in the  X-linked   PHEX  (phosphate regulating endopeptidase X-linked) gene, [ 2 ]  which encodes for a protein that regulates phosphate levels in the human body. [ 3 ]  phosphate is an essential mineral which plays a significant role in the formation and maintenance of bones and teeth, energy production and other important cellular processes. [ 4 ]  phosphate diabetes is a condition that falls under the category of  tubulopathies , which refers to the pathologies of the renal tubules. [ 5 ]  The mutated PHEX gene causes pathological elevations in  fibroblast growth factor 23 (FGF23) , [ 1 ]  a hormone that regulates phosphate  homeostasis  by decreasing the reabsorption of phosphate in the kidneys. [ 6 ]


Elevated levels of FGF23 in phosphate diabetes lead to an increase in phosphate excretion through urine, thus reducing the phosphate levels in blood. [ 5 ]  However, due to impaired activation of  vitamin D , which plays a crucial role in increasing intestinal  calcium  and phosphate absorption, [ 7 ]  patients with this disorder are unable to replenish the lost phosphate. This results in low absorption of phosphate from the  gastrointestinal system , [ 5 ]  leading to a deficiency of phosphate in the body and disrupting the full calcium-phosphate  metabolism  process.


A common symptom of phosphate diabetes is  short stature . [ 8 ]


Delayed growth and development are common symptoms of phosphate diabetes in children, resulting in stunted growth and a shorter stature compared to their peers. This symptom is typically one of the earliest indicators of the disorder and may require treatment with growth hormone therapy to promote normal growth and development. [ citation needed ]


Children with phosphate diabetes may start to walk late (at the age of one and a half years and later) due to impaired bone development. [ 9 ]


Children with phosphate diabetes may have a birth defect in which the bones in a baby's skull fuse together too early before the brain is fully formed.  This is known as  craniosynostosis  that may lead to  head deformities . [ 9 ]


As phosphate is essential for the formation and maintenance of healthy teeth, phosphate diabetes can lead to a wide range of  dental problems , including the formation of cavities,  abscesses , and  tooth decay . [ 10 ]


The deficiency of phosphate may affect muscles, resulting in  muscle weakness  and  fatigue . Patients may have difficulties in performing physical activities and may require physical therapy to improve muscle strength and function. [ 9 ]


Due to phosphate deficiency, patients' bones in the legs may become fragile and brittle, which leads to a characteristic  bowing of the legs . [ 5 ]


In phosphate diabetes, the softening of the bones can lead to  bone pain , especially in the knees, hips, and lower back. [ 9 ]


In severe cases of phosphate diabetes, the deficiency of phosphate can lead to  deformities of the bones , resulting in conditions like  rickets  and  osteomalacia  (softening of the bones which leads to frequent fractures) and  kyphoscoliosis  (curvature of the spine). [ 5 ]


Phosphate diabetes that results from mutations in the PHEX gene is an  X-linked dominant  disorder, [ 11 ]  where the mutated gene is located on the  X chromosome  (one of the sex chromosomes). This inheritance trait is dominant, a single copy of the mutation from the parent is sufficient to cause the disorder in the child. [ 12 ]


As males have only one X chromosome (and one  Y chromosome ), while females have two X chromosomes, the inheritance of phosphate diabetes largely depends on the gender of the parent who carries the mutated gene. Affected fathers with phosphate diabetes are unable to pass the disease to their sons, but all of their daughters will be affected. In contrast, affected mothers with phosphate diabetes will pass the disease to half of their sons and half of their daughters statistically. [ 13 ]  Thus, this disorder most often occurs in females. [ 14 ]


While phosphate diabetes is typically inherited through X-linked dominant inheritance, in some rare cases, the disorder may occur  sporadically , meaning that there is no family history of the diseased condition. [ 15 ]  This may happen due to a new mutation in the PHEX gene which arises during fetal development or due to other genetic factors. [ citation needed ]


phosphate diabetes is caused by a genetic mutation in the  PHEX gene  located on the  X chromosome . The PHEX gene encodes for an enzyme called PHEX – phosphate regulating endopeptidase X-linked, which is involved in the regulation of phosphate metabolism in the body. [ 16 ]


An occurrence of PHEX gene mutation can lead to an increase in levels of fibroblast growth factor 23 (FGF23), [ 17 ]  which is a growth factor that regulates phosphate and vitamin D metabolism. Increased levels of FGF23 leads to increase renal phosphate excretion and decrease intestinal phosphate absorption: [ 18 ]


FGF23 acts on the kidneys to reduce the expression of  sodium/phosphate co-transporters  (NaPi-2a and NaPi-2c) in the proximal tubules. [ 19 ]  As these co-transporters are responsible for reabsorbing phosphate from urine back into the bloodstream, a decrease in their expression would reduce the amount of phosphate being reabsorbed back to blood, hence increasing the phosphate concentration in the urine being excreted ( hypophosphatemia ). [ citation needed ]


FGF23  acts on the intestines to reduce the expression of the  sodium-phosphate co-transporter (NaPi-2b)  in the  brush border membrane  of  enterocytes , [ 20 ]  which is an important site for nutrient absorption. This transporter facilitates the absorption of phosphate from digested food in the small intestines into the bloodstream. Therefore, reduced activity of the transporter would lower the amount of phosphate being absorbed into the blood, which in turn increases the amount of phosphate excreted in the faeces. [ citation needed ]


In addition, increased levels of FGF23 would affect vitamin D metabolism and inhibit the action of vitamin D. [ 21 ]  Vitamin D needs to be converted into its activated form,  1,25-dihydroxyvitamin D , to perform its role of regulating calcium and phosphate absorption in the intestines. [ 22 ]  A series of  enzymatic reactions  are required for the activation of vitamin D, and enzymes like  25-hydroxyvitamin D-1α-hydroxylase (CYP27B1)  and  1,25-dihydroxyvitamin D-24-hydroxylase (CYP24A1)  play an active role in these reactions. [ 23 ]  However, high levels of FGF23 in blood hinders the activation of vitamin D: [ 24 ]


FGF23 inhibits the catalytic activity of CYP27B1 in activating vitamin D in the kidneys through a signalling pathway that involves the  FGF receptor  and downstream intracellular signalling molecules (e.g.  FGFRs ,  MAPK ,  PI3K  etc.). [ 25 ]  This leads to a decreased levels of activated vitamin D (1,25-dihydroxyvitamin D), which lowers the activity of vitamin D and slows down the absorption of calcium and phosphate in the small intestines. [ citation needed ]


FGF23 stimulates the activity of CYP24A1 in breaking down the activated form of vitamin D. [ 26 ]  As the availability of activated vitamin D in blood is decreased, the absorption of phosphate into bloodstream is hindered, which further intensifies the systemic  phosphate deficiency  in the patient's body. [ citation needed ]


Due to the increased phosphate loss through the excretion of urine and faeces, as well as the reduced absorption of phosphate into blood due to the reduced activity of vitamin D, patients' plasma phosphate levels become lower than normal. This results in a chronic systemic phosphate deficiency that may cause a variety of symptoms with varying degrees of intensity. [ citation needed ]


When the patients' body appear symptoms of phosphate diabetes, they are recommended to go to the hospital for consultation and body check. Doctors specialised in  endocrinology  and  orthopaedics  can examine the patient's health condition, and prescribe suitable medicine or arrange referral for further checking. [ citation needed ]


In phosphate diabetes patients' blood, the phosphate levels are level while calcium and  parathyroid hormone  (PTH) levels remain to be normal. Blood tests can be performed to measure if there are any abnormalities with the phosphate levels in blood. [ 27 ]


In the urine of phosphate diabetes patients, excess amount of phosphate can be detected due to the impaired reabsorption of phosphate in the kidneys. By testing for the concentration of phosphate in urine, whether the patient is suffering from phosphate diabetes can be determined. [ citation needed ]


X-ray scans of bones can be useful for doctors to assess abnormalities in bone density and detect bone deformities, [ 28 ]  such as the bowing of the legs, curvature of spines, which are the symptoms of phosphate diabetes.


Patients with  mutations  in the PHEX gene usually possess phosphate diabetes. Through the  genetic analysis  of  X chromosome (s) of patients, it can confirm a diagnosis of phosphate diabetes. [ 29 ]  At the same time, other family members who are at risk of the disease can be identified. [ citation needed ]


Since phosphate diabetes is an inheritable condition, immediate  genetic analysis  should be performed on a child after birth if one of the parents has been diagnosed with the disorder during childhood. Earlier diagnosis of the disease can facilitate more effective treatments, hence minimising its impact on the child. [ citation needed ]


phosphate diabetes is a rare condition that affects approximately 1 in 20000-25000 individuals, [ 33 ]  making it relatively difficult to study  epidemiologically . However, advances in  genetic testing  and improved awareness of the condition have led to increased diagnosis rates in recent years. [ citation needed ]


While phosphate diabetes can affect individuals of any race or ethnicity, [ 34 ]  it is more common in certain populations, such as those of European and Middle Eastern descent. [ 35 ]


Pilotto syndrome  is a rare syndrome which affects the  face ,  heart , and  back . The syndrome can cause a  cleft lip and palate ,  scoliosis , and  mental retardation . The  Office of Rare Diseases  and  National Institutes of Health  have classified this syndrome as affecting less than 200,000 people in the  United States . [ 2 ]


Polymelia  is a  birth defect  in which an affected individual has more than the usual number of limbs. It is a type of  dysmelia . In humans and most land-dwelling vertebrates, this means having five or more limbs. The extra limb is most commonly shrunken and/or deformed. The term is from Greek πολυ- "many", μέλεα "limbs".


Sometimes an embryo started as  conjoined twins , but one twin degenerated completely except for one or more limbs, which end up attached to the other twin.


Sometimes small extra legs between the normal legs are caused by the body axis forking in the  dipygus  condition.


Notomelia  (from Greek for "back-limb-condition") is polymelia where the extra limb is rooted along or near the midline of the back. [ citation needed ]  Notomelia has been reported in  Angus  cattle often enough to be of concern to farmers. [ 1 ]


Cephalomelia  (from Greek for "head-limb-condition") is polymelia where the extra limb is rooted on the head. [ 2 ]


Tetrapod  legs evolved in the  Devonian  or  Carboniferous  geological period from the  pectoral fins  and  pelvic fins  of their  crossopterygian  fish ancestors.
 Fish fins  develop along a "fin line", which runs from the back of the head along the midline of the back, round the end of the tail, and forwards along the underside of the tail, and at the  cloaca  splits into left and right fin lines which run forwards to the gills. In the paired ventral part of the fin line, normally only the pectoral and pelvic fins survive (but the  Devonian   acanthodian  fish  Mesacanthus  developed a third pair of paired fins); but along the non-paired parts of the fin line,  other fins  develop.


In  tetrapods , only the four paired fins normally persisted, and became the four legs. Notomelia and cephalomelia are  atavistic  reappearances of  dorsal fins . Some other cases of polymelia are extra development along the paired part of the fin lines, or along the ventral posterior non-paired part of the fin line.


Many mythological creatures like  dragons ,  winged horses , and  griffins  have six limbs: four legs and two wings. The dragon's science is discussed in  Dragons: A Fantasy Made Real . Additionally, angels are often depicted with two arms, two legs, and two wings.


In  Greek Mythology :


Sleipnir , Odin's horse in  Norse mythology , has eight normal horse legs, and is usually depicted with limbs twinned at the shoulder or hip.


Several  Hindu  deities are depicted with multiple arms and sometimes also multiple legs.


The  Ponseti method  is a manipulative technique that corrects congenital  clubfoot  without invasive surgery. It was developed by  Ignacio V. Ponseti  of the   University of Iowa Hospitals and Clinics , US, in the 1950s, and was repopularized in 2000 by John Herzenberg in the US and Europe and in Africa by NHS surgeon Steve Mannion. It is a standard treatment for clubfoot. [ citation needed ]


Ponseti treatment was introduced in UK in the late 1990s and widely popularized around the country by NHS physiotherapist Steve Wildon.
The manipulative treatment of club foot deformity is based on the inherent properties of the connective tissue, cartilage, and bone, which respond to the proper mechanical stimuli created by the gradual reduction of the deformity. The ligaments, joint capsules, and tendons are stretched under gentle manipulations. A plaster cast is applied after each manipulation to retain the degree of correction and soften the ligaments. The displaced bones are thus gradually brought into the correct alignment with their joint surfaces progressively remodeled yet maintaining congruency. After two months of manipulation and casting the foot appears slightly over-corrected. After a few weeks in splints, however, the foot looks normal. [ citation needed ]


Proper foot manipulations require a thorough understanding of the anatomy and kinematics of the normal foot and of the deviations of the tarsal bones in the clubfoot. Poorly conducted manipulations will further complicate the clubfoot deformity. The non-operative treatment will succeed better if it is started a few days or weeks after birth and if the podiatrist understands the nature of the deformity and possesses manipulative skill and expertise in plaster-cast applications. [ 1 ]


The Ponseti technique is painless, fast, cost-effective and successful in almost 100% of all congenital clubfoot cases. The Ponseti method is endorsed and supported by the World Health Organization, [ 2 ] [ 3 ]  National Institutes of Health, [ 4 ]  American Academy of Orthopedic Surgeons, [ 5 ]  Pediatric Orthopedic Society of North America, [ 6 ]  European Pediatric Orthopedic Society, [ 7 ]   CURE International , [ 8 ]  STEPS Charity Worldwide, [ 9 ]  STEPS Charity South Africa, [ 10 ]  and A Leg to Stand On (India). [ 11 ]


The  calcaneal  internal rotation (adduction) and  plantar  flexion is the key deformity. The foot is adducted and plantar-flexed at the subtalar joint, and the goal is to abduct the foot and dorsiflex it. In order to achieve correction of the clubfoot, the calcaneus should be allowed to rotate freely under the  talus bone , which also is free to rotate in the ankle mortise. The correction takes place through the normal arc of the subtalar joint. This is achieved by placing the index finger of the operator on the medial  malleolus  to stabilize the leg and levering on the thumb placed on the lateral aspect head of the talus while abducting the forefoot in supination. Forcible attempts at correcting the heel varus by abducting the forefoot while applying counter pressure at the  calcaneocuboid  joint prevents the calcaneus from abducting and therefore everting.


Foot cavus increases when the forefoot is pronated. If cavus is present, the first step in the manipulation process is to supinate the forefoot by gently lifting the dropped first  metatarsal  to correct the cavus. Once the cavus is corrected, the forefoot can be abducted.


Pronation of the foot also causes the calcaneus to jam under the talus. The calcaneum cannot rotate and stays in varu; the cavus then increases, resulting in a bean-shaped foot. At the end of the first step, the foot is maximally abducted but never pronated.


The manipulation is carried out in the cast room, with the baby having been fed just prior to the treatment or even during the treatment. After the foot is manipulated, a long leg cast is applied to hold the correction. Initially, the short leg component is applied. The cast should be snug with minimal but adequate padding. The authors [ who? ]  paint or spray the limb with tincture of benzoin to allow adherence of the padding to the limb. The authors [ who? ]  prefer to apply additional padding strips along the medial and lateral borders to facilitate safe removal of the cast with a cast saw. The cast must incorporate the toes right up to the tips but not squeeze the toes or obliterate the transverse arch. The cast is molded to contour around the heel while abducting the forefoot against counter pressure on the lateral aspect of the head of the talus. The knee is flexed to 90° for the long leg component of the cast. The parents can soak these casts for 30–45 minutes prior to removal with a plaster knife. The authors' [ who? ]  preferred method is to use the oscillating plaster saw for cast removal. The cast is bivalved and removed. The cast then is reconstituted by coapting the two halves. This allows for monitoring of the progress of the forefoot abduction and, in the later stages, the amount of dorsiflexion or equinus correction.


Forcible correction of the equinus (and cavus) by dorsiflexion against a tight Achilles tendon results in a spurious correction through a break in the midfoot, resulting in a rocker-bottom foot. The cavus should be separately treated as outlined in step 2, and the equinus should be corrected without causing a midfoot break. It generally takes up to 4–7 casts to achieve maximum foot abduction. The casts are changed weekly. The foot abduction (correction) can be considered adequate when the thigh-foot axis is 60°. After maximal foot abduction is obtained, most cases require a percutaneous Achilles tenotomy. This is performed in the cast room under aseptic conditions. The local area is anesthetized with a combination of a topical lignocaine preparation (e.g. EMLA cream) and minimal local infiltration of lidocaine. The tenotomy is performed through a stab incision with a round tip (#6400) Beaver blade. The wound is closed with a single absorbable suture or with adhesive strips. The final cast is applied with the foot in maximum dorsiflexion, and the foot is held in the cast for 2–3 weeks.


Following the manipulation and casting phase, the feet are fitted with open-toed straight-laced shoes attached to a  Denis Browne bar . The affected foot is abducted (externally rotated) to 70° with the unaffected foot set at 45° of abduction. The shoes also have a heel counter bumper to prevent the heel from slipping out of the shoe. The shoes are worn for 23 hours a day for three months and are worn at night and during naps for up to three years.


In 10–30% of cases, a tibialis anterior tendon transfer to the lateral cuneiform is performed when the child is approximately three years of age. This gives lasting correction of the forefoot, preventing metatarsus adductus and foot inversion. This procedure is indicated in a child aged 2–2.5 years with dynamic supination of the foot. Prior to surgery, cast the foot in a long leg cast for a few weeks to regain the correction.


Porencephaly  is an extremely rare  cephalic disorder  involving  encephalomalacia . [ 1 ]  It is a  neurological disorder  of the central nervous system characterized by  cysts  or  cavities  within the  cerebral hemisphere . [ 2 ]  Porencephaly was termed by Heschl in 1859 to describe a cavity in the human brain. [ 3 ]  Derived from  Greek  roots, the word  porencephaly  means 'holes in the brain'. [ 4 ]   The cysts and cavities (cystic brain lesions) are more likely to be the result of destructive (encephaloclastic) cause, but can also be from abnormal development (malformative), direct damage, inflammation, or hemorrhage. [ 5 ]  The cysts and cavities cause a wide range of physiological, physical, and neurological symptoms. [ 6 ]  Depending on the patient, this disorder may cause only minor neurological problems, without any disruption of intelligence, while others may be severely disabled or die before the second decade of their lives. However, this disorder is far more common within infants, and porencephaly can occur both before or after birth. [ 2 ]


Patients diagnosed with porencephaly display a variety of symptoms, from mild to severe effects on the patient. Patients with severe cases of porencephaly have  epileptic seizures  and developmental delays, whereas patients with a mild case of porencephaly display little to no seizures and typical neurodevelopment. Infants with extensive defects show symptoms of the disorder shortly after birth, and the diagnosis is usually made before the age of 1. [ 2 ] [ 7 ]


The following text lists out common signs and symptoms of porencephaly in affected individuals along with a short description of certain terminologies. [ 2 ] [ 6 ] [ 7 ] [ 8 ]


Porencephaly is a rare disorder. The exact prevalence of porencephaly is not known; however, it has been reported that 6.8% of patients with  cerebral palsy  or 68% of patients with  epilepsy  and congenital vascular  hemiparesis  have porencephaly. [ 5 ]  Porencephaly has a number of different, often unknown, causes including absence of brain development and destruction of brain tissue. With limited research, the most commonly regarded cause of porencephaly is disturbances in blood circulation, ultimately leading to brain damage. [ 6 ]  However, a number of different and multiple factors such as abnormal brain development or damage to the brain tissue can also affect the development of porencephaly. [ 2 ]


The following text lists out potential risk factors of developing porencephaly and porencephalic cysts and cavities along with brief description of certain terminologies. [ 3 ] [ 6 ] [ 7 ] [ 9 ]


Cysts or cavities can occur anywhere within the brain and the locations of these cysts depend highly on the patient. Cysts can develop in the  frontal lobe ,  parietal lobe ,  forebrain ,  hindbrain ,  temporal lobe , or virtually anywhere in the  cerebral hemisphere . [ 7 ]


From recent studies,  de novo  and inherited mutations in the gene  COL4A1 , suggesting genetic predisposition within the family, that encodes  type IV collagen α1 chain  has shown to be associated with and present in patients with porencephaly.  COL4A1  mutation causes a variety of  phenotypes , including porencephaly, infantile  hemiplegia , and  cerebral small vessel diseases  involving both  stroke  and  infarction . [ 6 ]  Abnormal gene expression of  COL4A1  can contribute to the development of porencephaly.  COL4A1  gene expresses a type IV collagen (basement protein) that is present in all tissue and blood vessels and is extremely important for the structural stability of vascular  basement membranes . The  COL4A1  protein provides a strong layer around blood vessels. [ 10 ]  The mutation can weaken the blood vessels within the brain, elevating the probability of a  hemorrhage , and eventually promoting internal bleeding then leading to porencephaly during neurodevelopment of infantile stage. [ 6 ]  Therefore, the formation of cavities can be a result of hemorrhages which promote  cerebral degeneration . [ 10 ]  In a mouse model, mouse with  COL4A1  mutations displayed  cerebral hemorrhage , porencephaly, and abnormal development of vascular basement membranes, such as uneven edges, inconsistent shapes, and highly variable thickness. [ 6 ]  Purposely causing a mutation in the  COL4A1  gene caused several mouse to develop cerebral hemorrhage and porencephaly-like diseases. Though, there is no direct correlation between mutations of the  COL4A1  gene, it appears that it has an influential effect on the development of porencephaly. [ 11 ] [ 12 ] [ 13 ]


Another genetic mutation,  factor V G1691A  mutation, has been reported to show possible association to the development of porencephaly. A mutation in  factor V G1691A  increases the risk of  thrombosis , blood clots, in  neonates , infants, and children. [ 5 ]  Therefore, 76 porencephalic and 76 healthy infants were investigated for  factor V G1691A  mutation along with other different  prothrombotic risk factors . The results indicated that there was  higher prevalence of the  factor V G1691A  mutation in the porencephalic patient group. The prediction that childhood porencephaly is caused by  hypercoagulable state , a condition where one has a higher chance of developing blood clots, was supported by the significance of the  factor V G1691A  mutation. Also, pregnant women in hypercoagulable state can cause the fetus to have the same risks, therefore possibly causing fetal loss, brain damage, lesions, and infections that lead to porencephaly.  However, other different prothrombotic risk factors individually did not reach statistical significance to link it to the development of porencephaly, but a combination of multiple prothrombotic risk factors in the porencephaly group was significant. Overall,  factor V G1691A  mutation has been linked to the development of porencephaly. However, this one mutation is not the cause of porencephaly, and whether further prothrombiotic risk factors are associated with porencephaly still remains unknown. [ 5 ]


In utero  exposure to  cocaine  and other  street drugs  can lead to porencephaly. [ 14 ]


The presence of porencephalic cysts or cavities can be detected using trans-illumination of the skull of infant patients. Porencephaly is usually diagnosed clinically using the patients and families history, clinical observations, or based on the presence of certain characteristic neurological and physiological features of porencephaly. Advanced medical imaging with  computed tomography  (CT),  magnetic resonance imaging  (MRI), or with  ultrasonography  can be used as a method to exclude other possible neurological disorders. The diagnosis can be made antenatally with ultrasound. Other assessments include memory, speech, or intellect testing to help further determine the exact diagnose of the disorder. [ 2 ]


Currently, there is no cure for porencephaly because of the limited resources and knowledge about the neurological disorder. However, several treatment options are available. Treatment may include physical therapy, rehabilitation, medication for  seizures  or  epilepsy ,  shunt (medical) , or  neurosurgery  (removal of the cyst). [ 2 ]  According to the location, extent of the lesion, size of cavities, and severity of the disorder, combinations of treatment methods are imposed. In porencephaly patients, patients achieved good seizure control with appropriate drug therapy including  valproate ,  carbamazepine , and  clobazam . [ 6 ] [ 7 ]  Also,  anti-epileptic drugs  served as another positive method of treatment. [ 7 ]


The severity of the symptoms associated with porencephaly varies significantly across the population of those affected, depending on the location of the cyst and damage of the brain. For some patients with porencephaly, only minor neurological problems may develop, and those patients can live normal lives. Therefore, based on the level of severity, self-care is possible, but for the more serious cases lifelong care will be necessary. [ 2 ]  For those that have severe disability, early diagnosis, medication, participation in rehabilitation related to fine-motor control skills, and communication therapies can significantly improve the symptoms and ability of the patient with porencephaly to live a normal life. Infants with porencephaly that survive, with proper treatment, can display proper communication skills, movement, and live a normal life. [ citation needed ]


Under the United States federal government, the National Institute of Neurological Disorders and Stroke and National Institute of Health are involved in conducting and supporting research related to normal and abnormal brain and nervous system development. Information gained from the research is used to develop understanding of the mechanism of porencephaly and used to offer new methods of treatment and prevention for developmental brain disorders such as porencephaly. [ 2 ]


Potocki–Lupski syndrome  ( PTLS ), also known as  dup(17)p11.2p11.2 syndrome ,  trisomy 17p11.2  or  duplication 17p11.2 syndrome , is a  contiguous gene syndrome  involving the  microduplication  of  band  11.2 on the  short arm  of human  chromosome 17  (17p11.2). [ 1 ]  The duplication was first described as a  case study  in 1996. [ 2 ]  In 2000, the first study of the disease was released, [ 3 ]  and in 2007, enough patients had been gathered to complete a comprehensive study and give it a detailed clinical description. [ 1 ]  PTLS is named for two researchers involved in the latter phases, Drs.  Lorraine Potocki  and  James R. Lupski  of  Baylor College of Medicine . [ 1 ] [ 4 ]


PTLS was the first predicted  reciprocal  of a  homologous recombination  ( microdeletion  or  microduplication ) where both reciprocal recombinations result in a contiguous gene syndrome. [ 1 ]  Its reciprocal disease is  Smith–Magenis syndrome  (SMS), in which the chromosome portion duplicated in PTLS is deleted altogether. [ 3 ]


Potocki–Lupski syndrome is considered a  rare disease , [ 5 ] [ 6 ]  predicted to appear in at least 1 in 20,000 humans. [ 7 ]


Symptoms of the syndrome include  intellectual disability ,  autism , [ 1 ] [ 8 ]  and other disorders unrelated to the listed symptoms.


Clinically, PTLS presents as a milder syndrome than SMS, with distinct characteristics, though PTLS can be mistaken for SMS. [ 1 ]  Both syndromes are characterized by multiple  congenital abnormalities  and  intellectual disability . A key feature which appears in 80% of cases is  autism spectrum disorder . [ 9 ]  Other unique features of Potocki–Lupski syndrome include  infantile hypotonia ,  sleep apnea ,  structural cardiovascular anomalies ,  cognitive deficits , [ 10 ]  abnormal  social behaviors , [ 9 ]   learning disabilities ,  attention-deficit disorder ,  obsessive-compulsive behaviours ,  malocclusions ,  short stature  and  failure to thrive . [ 1 ] [ 11 ]


After noting that autism is commonly associated with PTLS, researchers at the  Centro de Estudios Científicos  and the  Austral University of Chile   genetically engineered  a PTLS " model mouse " where the  syntenic  chromosome segment was duplicated, and examined the  social behaviours  of these mice versus those without the anomaly (the " wild-type "). [ 9 ]  One human autism-related symptom is abnormal  reciprocal   social interaction . [ 9 ]  The researchers observed that the  genetically-engineered  mice of both sexes had a slight ( statistically insignificant ) impairment of their preference of a  social target  (i.e., a living, breathing mouse) over an  inanimate  one — the average human will prefer the social target — and preferred to explore newly introduced mice instead of familiar ones, unlike the typical human and mouse preference of a friend over a stranger, demonstrating a change in their liking of  social novelty . They also found that male mice, in some scenarios, showed increased  anxiety  and  dominant behaviour  than the  control group . Anatomically, the engineered mice had a decreased  brain-to-body mass ratio  and an alteration in the  expression  of several genes in the  hippocampus . [ 9 ] [ 12 ]


Both Potocki–Lupski and Smith–Magenis syndromes arise through a faulty  non-allelic homologous recombination  mechanism. [ 13 ]  Both appear to involve a 1.3-3.7 Mb  chromosome section in  17p11.2  that includes the  retinoic acid  inducible 1  ( RAI1 ) gene. [ 14 ]  Other  candidate genes  have been identified within the duplicated section, including  SREBF1 ,  DRG2 ,  LLGL1 ,  SHMT1  and  ZFP179 . [ 9 ]


In mice of the subfamily  Murinae , a 32-34 cM  region of chromosome 11 is  syntenic  to 17p11.2, meaning that they contain the same genes in the same order and orientation. [ 12 ]  This conserved sequence has been exploited to learn more about SMS and PTLS. Through genetic studies on both  laboratory mice  and humans, it has been discovered that  RAI1  is likely the gene responsible for these syndromes. For example, in one study, it was shown that mice with 2 copies of the  RAI1  gene and 3 copies of each of the other 18 genes in the described  translocated  region of chromosome 11 appeared and behaved like the control mice with the described region intact. [ 11 ] [ 15 ]  In other words,  RAI1  is  dosage -sensitive. This provides evidence that it is the number of  RAI1   copies  present that affects the symptoms of PTLS and SMS. It is therefore believed that  RAI1  is the critical gene involved in these disorders; [ 1 ]  however, since no cases of  RAI1  duplication alone have been identified, this has not been concluded. [ 14 ]


One group has noted that, in a mouse model, the  flanking genes  in the duplicated segment were also  overexpressed , suggesting some new  candidates  for analysis, including  MFAP4 ,  TTC19  and  GJA12 . [ 9 ]


The duplication involved in PTLS is usually large enough to be detected through  G-banding  alone, [ 16 ]  though there is a high  false negative  rate. [ 1 ]  To ascertain the diagnosis when  karyotyping  results are unclear or negative, more sophisticated techniques such as  subtelomeric   fluorescent in-situ hybridization  analysis and  array comparative genomic hybridization  (aCGH) may be used. [ 17 ]


Potocki–Shaffer syndrome (PSS) , also known as  DEFECT11 syndrome  or  chromosome 11p11.2 deletion syndrome , [ 1 ]  is a rare  contiguous gene syndrome  that results from the  microdeletion  of section 11.2 on the  short arm  of  chromosome   11  (11p11.2). The syndrome has its name from Dr.  Lorraine (Lori) Potocki  and Dr. Lisa Shaffer who discovered the deletion on the 11th chromosome and studied the impacts. [ 2 ]


The deletion of this combination of genes results in several distinctive  congenital  features, occasional defects in the heart, kidneys, and urinary tract. The disorder is associated with an enlarged  parietal foramina  which can cause openings in the two bones that form the top and sides of the skull. These abnormal openings form extra "soft spots" on the head, in addition to the two that newborns normally have, and unlike the usual newborn soft spots, the enlarged parietal foramina remain open throughout life. Other signs can include multiple mostly noncancerous  benign   bone tumours  called  osteochondromas  ( exostosis ),  developmental delay ,  vision disorders  and  craniofacial abnormalities . [ 2 ]  It is classified as a  rare disease . [ 2 ] [ 3 ]


The signs and symptoms of Potocki–Shaffer syndrome vary widely. In addition to multiple osteochondromas and enlarged parietal foramina, affected individuals often have  intellectual disability  and delayed development of speech,  motor skills  (such as sitting and walking), and  social skills . Many people with this condition have distinctive facial features, which can include a wide, short skull ( brachycephaly ); a prominent forehead; a narrow bridge of the nose; a shortened distance between the nose and upper lip (a short  philtrum ); and a  downturned mouth . Less commonly, Potocki–Shaffer syndrome causes  vision problems , additional skeletal abnormalities, and defects in the  heart ,  kidneys , and  urinary tract . [ 4 ]


Potocki–Shaffer syndrome follows an autosomal dominant inheritance pattern, which means a deletion of genetic material from one copy of  chromosome 11  is sufficient to cause the disorder. In some cases, an affected person inherits the chromosome with a deleted segment from an affected  parent . More commonly, the condition results from a deletion that occurs during the formation of  reproductive cells  (eggs and  sperm ) in a parent or in early  fetal development . These cases occur in people with no history of the disorder in their family. [ citation needed ]


Potocki–Shaffer syndrome can be detected through  array comparative genomic hybridization  (aCGH). [ citation needed ]


Some symptoms can be managed with  drug therapy ,  surgery  and  rehabilitation ,  genetic counselling , and  palliative care . [ 4 ]


Prader–Willi syndrome  ( PWS )  is a rare  genetic disorder  caused by a loss of function of specific genes on  chromosome 15 . [ 2 ]  In  newborns , symptoms include  weak muscles , poor feeding, and slow development. [ 2 ]  Beginning in childhood, those affected become constantly hungry, which often leads to  obesity  and  type 2 diabetes . [ 2 ]  Mild to moderate  intellectual impairment  and  behavioral problems  are also typical of the disorder. [ 2 ]  Often, affected individuals have a narrow forehead, small hands and feet, short height, and light skin and hair. Most are  unable to have children . [ 2 ]


About 74% of cases occur when part of the father's chromosome 15 is deleted. [ 2 ]  In another 25% of cases, the affected person has  two copies  of the maternal chromosome 15 from the mother and lacks the paternal copy. [ 2 ]  As parts of the chromosome from the mother are turned off through  imprinting , they end up with no working copies of certain genes. [ 2 ]  PWS is not generally  inherited , but rather the genetic changes happen during the formation of the  egg ,  sperm , or in early development. [ 2 ]  No risk factors are known for the disorder. [ 4 ]  Those who have one child with PWS have less than a 1% chance of the next child being affected. [ 4 ]  A similar mechanism occurs in  Angelman syndrome , except the defective chromosome 15 is from the mother, or two copies are from the father. [ 5 ] [ 6 ]


Prader–Willi syndrome has no cure. [ 7 ]  Treatment may improve outcomes, especially if carried out early. [ 7 ]  In newborns, feeding difficulties may be supported with  feeding tubes . [ 3 ]  Strict food supervision is typically required, starting around the age of three, in combination with an exercise program. [ 3 ]   Growth hormone therapy  also improves outcomes. [ 3 ]   Counseling  and medications may help with some behavioral problems. [ 3 ]   Group homes  are often necessary in adulthood. [ 3 ]


PWS affects between 1 in 10,000 to 30,000 people worldwide. [ 2 ]  The condition is named after Swiss physicians  Andrea Prader  and  Heinrich Willi  who, together with Alexis Labhart, described it in detail in 1956. [ 1 ]  An earlier description was made in 1887 by British physician  John Langdon Down . [ 8 ] [ 9 ]


PWS symptoms can range from poor muscle tone during infancy to behavioral problems in early childhood. Some symptoms often found in infants, besides poor muscle tone, are a lack of eye coordination; almond-shaped eyes; thin upper lip; and, due to poor muscle tone, lack of a strong sucking reflex. Their cries are weak, and they have difficulty waking up. [ 10 ]


More aspects seen in a clinical overview include hypotonia and abnormal neurologic function, hypogonadism, developmental and cognitive delays, hyperphagia and obesity, short stature, and behavioral and psychiatric disturbances. [ 11 ]


The following features and signs are indicators of PWS, although not all will be present: [ 12 ] [ 13 ]


Individuals with PWS are at risk of learning and attention difficulties. Curfs and Fryns (1992) conducted research into the varying degrees of  learning disability  found in PWS. [ 14 ]


Cassidy found that 40% of individuals with PWS have borderline/low average intelligence, [ 15 ]  a figure higher than the 32% found in Curfs and Fryns' study. [ 14 ]  However, both studies suggest that most individuals (50–65%) fall within the mild/borderline/low average intelligence range. [ citation needed ]


Children with PWS show an unusual cognitive profile. They are often strong in visual organization and perception, including reading and vocabulary, but their spoken language (sometimes affected by  hypernasality ) is generally poorer than their comprehension. A marked skill in completing  jigsaw puzzles  has been noted, [ 16 ] [ 17 ]  but this may be an effect of increased practice. [ 18 ]


Auditory information processing and sequential processing are relatively poor, as are arithmetic and writing skills, visual and  auditory short-term memory , and auditory  attention span . These sometimes improve with age, but deficits in these areas remain throughout adulthood. [ 16 ]


PWS may be associated with psychosis. [ 19 ]


PWS is frequently associated with a constant insatiable appetite, which persists no matter how much the patient eats, often resulting in  morbid obesity .  Caregivers need to strictly limit the patients' access to food, usually by installing locks on refrigerators and on all closets and cabinets where food is stored. [ 20 ]  It is the most common genetic cause of morbid obesity in children. [ 21 ]  Currently, no consensus exists as to the cause for this symptom, although genetic abnormalities in chromosome 15 disrupt the normal functioning of the  hypothalamus . [ 15 ]  Given that the hypothalamic  arcuate nucleus  regulates many basic processes, including appetite, a link may well exist. In the hypothalamus, nerve cells that produce  oxytocin , a hormone thought to contribute to satiety, are believed to be abnormal in people with PWS. [ 22 ]


People with PWS have high  ghrelin  levels, which are thought to contribute directly to the increased appetite, hyperphagia and obesity seen in this syndrome. [ 23 ]  Cassidy states the need for a clear delineation of behavioral expectations, the reinforcement of behavioural limits, and the establishment of regular routines.


The main mental-health difficulties experienced by people with PWS include compulsive behaviour (usually manifested in skin picking) and anxiety. [ 16 ] [ 24 ]  Psychiatric symptoms, for example, hallucinations, paranoia and depression, have been described in some cases [ 16 ]  and affect about 5–10% of young adults. [ 15 ]   Patients are also often extremely stubborn and prone to anger. [ 20 ]  Psychiatric and behavioural problems are the most common cause of hospitalization. [ 25 ]


Typically 70–90% of affected individuals develop behavioral patterns in early childhood. [ 11 ]  Aspects of these patterns can include stubbornness, temper tantrums, controlling and manipulative behavior, difficulty with change in routine and compulsive-like behaviors. [ 11 ]


Several aspects of PWS support the concept of a growth hormone deficiency. Specifically, individuals with PWS are obese with short stature, abnormal body composition, reduced fat-free mass, reduced lean body mass and total energy expenditure, and decreased bone density. PWS is characterized by hypogonadism. This is manifested as undescended testes in males and benign premature  adrenarche  in females. Testes may descend with time or can be managed with surgery or testosterone replacement. Adrenarche may be treated with hormone replacement therapy. [ citation needed ]


PWS is commonly associated with development of  strabismus . In one study, [ 26 ]  over 50% of patients had strabismus, mainly  esotropia .


Some individuals (often those with deletions) may have hypopigmented fundi due to  OCA2   haploinsufficiency .


PWS is related to an epigenetic phenomenon known as  imprinting . Normally, a fetus inherits an imprinted maternal copy of PW genes and a functional paternal copy of PW genes. Due to imprinting, the maternally inherited copies of these genes are virtually silent, and the fetus therefore relies on the expression of the paternal copies of the genes. [ 27 ] [ 28 ]  In PWS, however, there is mutation/deletion of the paternal copies of PW genes, leaving the fetus with no functioning PW genes. The PW genes are the  SNRPN  and  NDN  genes, along with clusters of  snoRNAs :  SNORD64 , SNORD107, SNORD108 and two copies of SNORD109, 29 copies of  SNORD116  (HBII-85) and 48 copies of  SNORD115  (HBII-52). These genes are located on  chromosome 15  located in the region 15q11-13. [ 29 ] [ 30 ] [ 31 ] [ 32 ]  This so-called PWS/AS region in the paternal chromosome 15 may be lost by one of several genetic mechanisms, which in the majority of instances occurs through chance mutation. Other, less common mechanisms include  uniparental disomy , sporadic  mutations , chromosome  translocations , and gene deletions. [ citation needed ]


Region 15q11-13 is implicated in both PWS and  Angelman syndrome  (AS). While PWS results from the loss of PW genes within this region on the paternal chromosome, loss of a different gene ( UBE3A ) within the same region on the maternal chromosome causes AS. [ 33 ]  PWS and AS represent the first reported instances of disorders related to imprinting in humans. [ citation needed ]


The risk to the sibling of an affected child of having PWS depends upon the genetic mechanism which caused the disorder. The risk to siblings is <1% if the affected child has a gene deletion or uniparental disomy, up to 50% if the affected child has a mutation of the imprinting control region, and up to 25% if a parental chromosomal translocation is present.  Prenatal testing  is possible for any of the known genetic mechanisms. [ citation needed ]


A  microdeletion  in one family of the snoRNA HBII-52 has excluded it from playing a major role in the disease. [ 34 ]


Studies of human and mouse model systems have shown deletion of the 29 copies of the  C/D box  snoRNA  SNORD116  (HBII-85) to be the primary cause of PWS. [ 35 ] [ 36 ] [ 37 ] [ 38 ] [ 39 ]


It is traditionally characterized by hypotonia, short stature, hyperphagia, obesity, behavioral issues (specifically  obsessive–compulsive disorder -like behaviors), small hands and feet, hypogonadism, and mild intellectual disability. [ 40 ]  However, with early diagnosis and early treatment (such as with growth hormone therapy), the prognosis for persons with PWS is beginning to change. Like autism, PWS is a spectrum disorder and symptoms can range from mild to severe and may change throughout the person's lifetime. Various organ systems are affected. [ 41 ]


Traditionally, PWS was diagnosed by clinical presentation. Currently, the syndrome is diagnosed through genetic testing; testing is recommended for newborns with pronounced hypotonia. Early diagnosis of PWS allows for early intervention and the early prescription of  growth hormone . Daily recombinant growth hormone (GH) injections are indicated for children with PWS. GH supports linear growth and increased muscle mass, and may lessen food preoccupation and weight gain. [ citation needed ]


The mainstay of diagnosis is  genetic testing , specifically DNA-based methylation testing to detect the absence of the paternally contributed PWS/AS region on chromosome 15q11-q13. Such testing detects over 97% of cases. Methylation-specific testing is important to confirm the diagnosis of PWS in all individuals, but especially those who are too young to manifest sufficient features to make the diagnosis on clinical grounds or in those individuals who have atypical findings. [ citation needed ]


PWS is often misdiagnosed due to its unfamiliarity in the medical community. Sometimes it is misdiagnosed as  Down syndrome , [ 21 ]   simply because of the relative frequency of Down syndrome compared to PWS. [ 21 ]


While PWS has no cure, several treatments are available to lessen the condition's symptoms. During infancy, subjects should undergo therapies to improve muscle strength. Speech and occupational therapy are also indicated. During the school years, children benefit from a highly structured learning environment and extra help. The largest problem associated with the syndrome is severe obesity.  Access to food must be strictly supervised and limited, usually by installing locks on all food-storage places including refrigerators. [ 20 ]  Physical activity in individuals with PWS for all ages is needed to optimize strength and promote a healthy lifestyle. [ 11 ]


An intranasal formulation of  betahistine  dihydrochloride received  orphan drug  designation from the US  Food and Drug Administration  (FDA) for the treatment of obesity associated with Prader–Willi syndrome. [ 42 ] [ 43 ] [ 44 ]


Prescription of daily recombinant GH injections are indicated for children with PWS. GH supports linear growth and increased muscle mass, and may lessen food preoccupation and weight gain. [ 45 ] [ 46 ] [ 47 ]


Because of severe obesity, obstructive  sleep apnea  is a common  sequela , and a  positive airway pressure  machine is often needed. A person who has been diagnosed with PWS may have to undergo surgical procedures. One surgery that has proven to be unsuccessful for treating the obesity is gastric bypass. [ 48 ]


Behavior and psychiatric problems should be detected early for the best results.  These issues are best when treated with parental education and training.  Sometimes medication is introduced as well.   Serotonin  agonists have been most effective in lessening temper tantrums and improving compulsivity. [ 11 ]


PWS affects one in 10,000 to one in 25,000 newborns. [ 40 ]  More than 400,000 people live with PWS. [ 49 ]


Despite its rarity, PWS has been often referenced in popular culture, partly due to curiosity surrounding the insatiable appetite and the obesity symptomatic of the syndrome.


Katie Price 's son Harvey is one well-known person with PWS. [ 51 ] [ 52 ]


The syndrome has been depicted and documented several times in television. A fictional individual with PWS featured in the episode "Dog Eat Dog" of the television series  CSI: Crime Scene Investigation , which aired in the US on 24 November 2005. [ 53 ]  In July 2007,  Channel 4  aired a 2006 documentary called  Can't Stop Eating , surrounding the everyday lives of two people with PWS, Joe and Tamara. [ 54 ]  In a 2010 episode of  Extreme Makeover: Home Edition ,   Sheryl Crow  helped  Ty Pennington  rebuild a home for a family whose youngest son, Ethan Starkweather, was living with the syndrome. [ 55 ]  In a 2012 episode of  Mystery Diagnosis  on the Discovery Health channel, Conor Heybach, who has Prader–Willi syndrome, shared how he was diagnosed with it. [ 56 ]


In  teratology , a  proboscis  is a blind-ended, tube-like structure, commonly located in the middle of the face. It is commonly seen in severe forms of  holoprosencephaly  that include  cyclopia  and is usually the result of abnormal development of the nose.


Proboscis formation is classified in four general types: holoprosencephalic proboscis, lateral nasal proboscis, supernumerary probosci, and disruptive proboscis.


A holoprosencephalic proboscis is found in  holoprosencephaly  (a condition in which the forebrain of the embryo fails to develop into two hemispheres as it should). In cyclopia or ethmocephaly, proboscis is an abnormally formed nose. In  cyclopia , a single eye in the middle of the face is associated with  arrhinia  (absence of the nose) and usually with proboscis formation above the eye. In  ethmocephaly , two separate hypoteloric eyes (eyes placed very close together) are associated with  arrhinia  and proboscis formation above the eye. In  cebocephaly , no proboscis formation occurs, but a single-nostril nose is present.


A lateral proboscis, also known as proboscis lateralis or lateral nasal proboscis, is a tubular proboscis-like structure and represents incomplete formation of one side of the nose; it is found instead of a nostril. The olfactory bulb is usually rudimentary on the side involved in the malformation. The tear duct, nasal bone, nasal cavity, vomer (the small thin bone separating the left and right nasal passages), maxillary sinus, ethmoidal sinuses, and another nasal structure known as the cribriform plate cells are often missing on this side as well. Ocular hypertelorism (eyes set far apart) may be present. The proboscis lateralis is a rare nasal anomaly.


A supernumerary proboscis, or accessory proboscis, is found when both nostrils are formed and there is a proboscis in addition to it. Accessory proboscis arise from a supernumerary olfactory placode.


A disruptive proboscis occurs if an hamartoneoplastic lesion (benign growths such as are found in disorders like neofibromatosis and tubular sclerosis) arises in the prosencephalon (forebrain) of the embryo in its early stages of development.


Progressive cardiac conduction defect   (PCCD)  is a hereditary cardiac condition marked by a progressive delay in impulse conduction via the His-Purkinje system, resulting in right or left  bundle branch block  (RBBB or LBBB),  syncope , and occasionally  sudden cardiac death . [ 1 ]


When progressive conduction abnormalities in people under 50 with structurally normal hearts are present but skeletal  myopathies  are absent, progressive cardiac conduction defect is primarily diagnosed, particularly if there is a family history of PCCD. [ 2 ]


At the moment, implanting an implantable  pacemaker  is the only proven treatment for PCCD, regardless of the underlying cause. [ 3 ]


Progressive familial intrahepatic cholestasis  (PFIC) is a group of  familial   cholestatic  conditions caused by defects in  biliary   epithelial  transporters.  The clinical presentation usually occurs first in  childhood  with progressive  cholestasis . This usually leads to  failure to thrive ,  cirrhosis , and the need for  liver transplantation . [ citation needed ]


Types of progressive familial intrahepatic cholestasis are as follows: [ citation needed ]


The onset of the  disease  is usually before age 2, but patients have been diagnosed with PFIC even into  adolescence .  Of the three entities, PFIC-1 usually presents earliest.  Patients usually present in early childhood with  cholestasis ,  jaundice , and  failure to thrive .  Intense  pruritus  is characteristic; [ 2 ]  in patients who present in adolescence, it has been linked with  suicide .  Patients may have  fat   malabsorption , leading to fat soluble  vitamin  deficiency, and complications, including  osteopenia . [ 3 ]


PFIC-1  is caused by a variety of  mutations  in  ATP8B1 , a  gene  coding for a P-type  ATPase   protein , FIC-1, that is responsible for  phospholipid  translocation across membranes. [ 4 ]   It was previously identified as clinical entities known as  Byler's disease  and  Greenland-Eskimo familial cholestasis .  Patients with PFIC-1 may also have watery  diarrhea , in addition to the clinical features below, due to FIC-1's expression in the  intestine .  How ATP8B1 mutation leads to cholestasis is not yet well understood. [ citation needed ]


PFIC-2  is caused by a variety of  mutations  in  ABCB11 , the  gene  that codes for the bile salt export pump, or BSEP.  Retention of bile salts within hepatocytes, which are the only cell type to express BSEP, causes hepatocellular damage and cholestasis. [ citation needed ]


PFIC-3  is caused by a variety of  mutations  in  ABCB4 , the gene encoding multidrug resistance protein 3 (MDR3), [ 5 ]  which codes for a  floppase  responsible for  phosphatidylcholine  translocation.  The defective phosphatidylcholine translocation leads to a lack of phosphatidylcholine in bile.  Phosphatidylcholine normally chaperones bile acids, preventing damage to the biliary epithelium.  The free or "unchaperoned" bile acids in bile of patients with MDR3 deficiency cause a  cholangitis .  Biochemically, this is of note, as PFIC-3 is associated with a markedly elevated GGT. [ citation needed ]


The  inheritance  pattern of all three forms of PFIC defined to date is  autosomal recessive . [ citation needed ]


Liver biopsies  typically show evidence of  cholestasis  (including bile plugs and bile infarcts), duct hypoplasia, hepatocellular injury, and Zone 3  fibrosis .  Giant cell change and other features of hepatocellular injury are more pronounced in PFIC-2 than in PFIC-1 or PFIC-3.  End-stage disease in all forms of PFIC defined to date is characterized by bridging fibrosis with duct proliferation in peri-portal regions. [ 6 ]


Biochemical markers include a normal  GGT  for PFIC-1 and -2, with a markedly elevated GGT for PFIC-3.  Serum  bile acid  levels are grossly elevated.  Serum  cholesterol  levels are typically not elevated, as is seen usually in cholestasis, as the  pathology  is due to a transporter as opposed to an anatomical problem with biliary cells. [ citation needed ]


Initial treatment is supportive, with the use of agents to treat  cholestasis  and  pruritus , including the following: [ citation needed ]


The partial external biliary diversion (PEBD) procedure is a surgical approach that diverts bile from the gallbladder externally into an ileostomy bag. [ 7 ]


Patients should be supplemented with fat-soluble vitamins, and occasionally  medium-chain triglycerides  in order to improve growth. When liver synthetic dysfunction is significant, patients should be listed for  transplantation .  Family members should be tested for PFIC mutations, in order to determine risk of transmission. [ citation needed ]


The disease is typically progressive, leading to fulminant  liver  failure and death in childhood, in the absence of  liver transplantation .  Hepatocellular carcinoma  may develop in PFIC-2 at a very early age; even toddlers have been affected. [ citation needed ]


Proteus syndrome  is a rare genetic disorder [ 1 ]  that can cause tissue overgrowth involving all three  embryonic lineages . Patients with Proteus syndrome tend to have an increased risk of embryonic tumor development. [ 2 ]  The clinical symptoms and  radiographic  findings of Proteus syndrome are highly variable, as are its orthopedic manifestations. [ 3 ] [ 4 ]


Only a few more than 200 cases have been confirmed worldwide, with estimates that about 120 people are currently alive with the condition. [ 5 ]  As attenuated forms of the disease may exist, there could be many people with Proteus syndrome who remain undiagnosed. Those most readily diagnosed are also the most severely disfigured.


The syndrome is named after the Greek sea god  Proteus , who could change his shape. The condition appears to have been first described in the American medical literature by Samia Temtamy and John Rogers in 1976. [ 6 ] [ 7 ]  American pathologist  Michael Cohen  described it in 1979. [ 8 ]


Proteus syndrome causes an overgrowth of skin, bones, muscles, fatty tissues, and blood and  lymphatic vessels . Proteus syndrome is a progressive condition wherein children are usually born without any obvious deformities. Tumors of skin and bone growths appear as they age typically in early childhood. The musculoskeletal manifestations are cardinal for the diagnosis of Proteus syndrome. [ 3 ]  The severity and locations of these asymmetrical growths vary greatly but typically the skull, one or more limbs, and soles of the feet will be affected. There is a risk of premature death in affected individuals due to  deep vein thrombosis  and  pulmonary embolism  caused by the vessel malformations that are associated with this disorder. Because of carrying excess weight and enlarged limbs,  arthritis  and muscle pain may also be symptoms. Further risks may occur due to the mass of extra tissue. [ citation needed ]


The disorder does not uniformly cause learning impairments: the distribution of intelligence deficits among those with Proteus syndrome appears higher than that of the general population. This is difficult to determine with statistical significance. [ 9 ]  In addition, the presence of visible deformity hurt the social experiences of the affected individual, causing emotional difficulties,  social rejection  and stigma. [ citation needed ]


Affected individuals are at increased risk for developing certain tumors including unilateral  ovarian cystadenomas ,  testicular tumors ,  meningiomas , and monomorphic  adenomas  of the  parotid gland . [ citation needed ]


Hemimegalencephaly  is often found to be associated. [ 10 ]


The musculoskeletal manifestations of Proteus syndrome are frequent and recognizable. Patients tend to demonstrate a unique pattern of skeletal abnormalities. The orthopaedic features are usually bilateral, asymmetrical, and progressive, and involve all four limbs and the spine. Affected patients usually have localized periarticular limb distortions, limb length discrepancy, and spine deformity. Patients with Proteus syndrome can have regular bone configuration and contours despite the bone enlargement. [ 3 ]  Patients can also exhibit deformation of the skull in the form of  dolichocephaly  or elongated skull and facial abnormalities. Because of the rarity of the syndrome and the variability of signs, orthopaedic management should be individualized. [ 3 ]


In 2011 researchers determined the cause of Proteus syndrome. In 26 of 29 patients who met strict clinical criteria for the disorder, Lindhurst  et al.  identified an activating mutation in  AKT1   kinase  in a mosaic state. [ 11 ]


Previous research had suggested the condition linked to  PTEN  on  chromosome 10 , [ 12 ]  while other research pointed to  chromosome 16 . [ 13 ]  Before the findings regarding  AKT1  in 2011, other researchers expressed doubt regarding the involvement of  PTEN  or  GPC3 , which codes for  glypican 3  and may play a role in regulating cell division and growth regulation. [ 14 ] [ 15 ]


Many sources classify Proteus syndrome as a type of  nevus  syndrome. The  lesions  appear to be distributed in a mosaic manner. [ 20 ]  It has been confirmed that the disorder is an example of genetic  mosaicism . [ 11 ]


A team of doctors in Australia has trial-tested the drug  rapamycin  in the treatment of a patient said to have Proteus syndrome and have found it to be an effective remedy. [ 21 ]  However, the diagnosis of Proteus syndrome in this patient has been questioned by others. [ 22 ]


The Arqule Corporation developed the AKT1 inhibitor ARQ 092, which is being tested by a research team in the  National Human Genome Research Institute  at the  United States National Institutes of Health  in a  Phase 0  dose-finding trial. In earlier tests on tissue and cell samples obtained from patients, ARQ 092 reduced  phosphorylation  of AKT and downstream targets of AKT in as little as two hours. [ 23 ]  The Phase 0 trial opened in November 2015. [ 24 ]  This trial is based on  in vitro  data showing inhibition of AKT1 in  cell lines  from patients with Proteus syndrome. [ 25 ]


In a 1986 article in the  British Medical Journal ,  Michael Cohen  and J.A.R. Tibbles proposed the idea that  Joseph Merrick  (an Englishman known as the "Elephant Man") had Proteus syndrome. However, the exact condition that Joseph Merrick had is still not known with certainty. [ 26 ] [ 27 ]


Mandy Sellars  has been diagnosed by some doctors as having this condition. [ 5 ]  Her legs and feet have grown disproportionately since birth. However, in 2013, Sellars's case was profiled on British television in a special called  Shrinking My 17 Stone Legs , in which it was determined that Sellars's condition was not, in fact, Proteus syndrome, but rather the often-misdiagnosed  PIK3CA-related overgrowth spectrum , a syndrome caused by a  PIK3CA  gene mutation. [ citation needed ]


Pterin-4 alpha-carbinolamine dehydratase deficiency  (PCDD) is one of the known forms of  tetrahydrobiopterin deficiency . This condition is associated with mutations of the  PCBD1  gene. As of 2020, PCDD was the rarest form of BH4 deficiency in terms of cases described in medical literature. [ 1 ]


Patients with PCDD are mostly asymptomatic, although they may have transient neurologic deficits in infancy, and sometimes  hypomagnesemia  and nonautoimmune  diabetes mellitus  in puberty. [ 1 ]


Pterin-4 alpha-carbinolamine dehydratase deficiency causes  hyperphenylalaninemia  and therefore can be suspected upon finding elevated levels of phenylalanine. To distinguish it from other forms of BH4 deficiency, further analyses are made. PCDD is associated with elevatel levels of  primapterin , especially in urine, while  biopterin  levels range from low to normal, and  neopterin  levels from normal to high. [ 1 ]


Treatment involves a diet with a low  phenylalanine  content, and  sapropterin  to help normalize phenylalanine levels. Since phenylalanine levels in this disease have been reported to be only mildly elevated in the majority of patients, relaxation and discontinuation of phenylalanine-reduced diet and/or sapropterin supplementation can be attempted after the first year of life under careful monitoring of phenylalanine levels, according to a consensus guideline published in 2020. [ 1 ]


Radioulnar synostosis  is a rare condition where there is an abnormal connection ( synostosis ) between the  radius  and  ulna  bones of the  forearm . [ 1 ]  This can be present at birth ( congenital ), when it is a result of a failure of the bones to form separately, or following an injury (post-traumatic). [ 2 ]


It typically causes  restricted movement  of the forearm, in particular rotation ( pronation  and  supination ), though is usually not painful unless it causes  subluxation  of the  radial head . [ 1 ]  It can be associated with  dislocation  of the radial head which leads to limited elbow extension. [ 2 ]


Congenital radioulnar synostosis is rare, with approximately 350 cases reported in journals. It typically affects both sides (bilateral) and can be associated with other skeletal problems such as hip and knee abnormalities, finger abnormalities ( syndactyly  or  clinodactyly ), or  Madelung's deformity . [ 1 ]  It is sometimes part of known genetic syndromes such as  Klinefelter syndrome  (48,XXXY variant),  Apert ,  Williams ,  Cornelia de Lange , or  Holt–Oram . [ 1 ] [ 3 ]  It has been reported to run in families typically following an  autosomal dominant  inheritance pattern, which means that children of an affected parent have a 50% chance of having the condition. [ 3 ]  When associated with  amegakaryocytic thrombocytopenia , this inheritance has been found to be caused by mutations to the  HOXA11  gene. [ 4 ]  It is also one of the known manifestations of the  fetal alcohol spectrum disorder , which results from prenatal exposure to alcohol. [ 5 ] [ 6 ]


Post-traumatic cases are most likely to develop following surgery for a forearm  fracture ; this is more common with high-energy injuries where the bones are broken into many pieces ( comminuted ). [ 1 ]  It can also develop following soft tissue injury to the forearm where there is  haematoma  formation. [ citation needed ]


Diagnosis at birthday [ clarification needed ]  is best done using ultrasound technology. In younger children and adults, diagnosis is done with x-ray machine at the radioulnar bones. [ citation needed ]


It is sometimes possible to correct the problem with surgery, though this has high failure rates for treatment of post-traumatic radioulnar synostosis. [ 1 ]  Indication for the surgical treatment of congenital radioulnar synostosis include severe disability due to bilateral disorder or hyperpronation ≥ 90°. [ 7 ]


Renal dysplasia-limb defects syndrome  ( RL syndrome ), also known as  Ulbright–Hodes syndrome , [ 1 ]  is a very rare [ 2 ]   autosomal   recessive   congenital disorder . [ 3 ] [ 4 ]  It has been described in three infants, all of whom died shortly after birth. [ 5 ]


RL syndrome is characterized by  renal dysplasia ,  growth retardation ,  phocomelia  or  mesomelia , radiohumeral fusion (joining of  radius  and  humerus ),  rib  abnormalities, anomalies of the external  genitalia  and potter-like  facies  among many others. [ 5 ] [ 6 ]


RL syndrome is  inherited  in an autosomal recessive manner. [ 3 ]  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. [ citation needed ]


Renal hypoplasia  is a  congenital abnormality  in which one or both of the  kidneys  are  smaller than normal , [ 5 ]  resulting in a reduced  nephron  number [ 1 ]  but with normal  morphology . [ 4 ]


It is defined as abnormally small kidneys, where the size is less than two  standard deviations  below the expected mean for the corresponding  demographics , and the morphology is normal. [ 4 ] [ 1 ]  The severity of the disease depends on whether  hypoplasia  is unilateral or bilateral, and the degree of reduction in the number of  nephrons . [ 1 ]


Renal hypoplasia pertains to the reduction in the number of  renal lobes . The classification of renal hypoplasia establishes four types, termed simple, oligomeganephronic, segmental, and cortical. [ citation needed ]


Simple hypoplasia is characterized by either one  kidney  weighing 50% or less of that of the normal, or the combined weight of both kidneys being less than 33% of that of the normal. Often accompanied by  hypertension . The number of  lobules  and  calyces  is reduced to five or fewer, compared to the usual ten or more. Enlargement of the  nephrons  is not present in this type, considering it is associated with  oligomeganephronia . The  histology  is normal.  Cysts  or  dysplasia  are absent and apart from its decreased size, every other facet of the kidneys is unaffected. If unilateral, the contralateral kidney can undergo  hypertrophy  to compensate for the affected kidney, and renal function stays normal. If bilateral, progressive  renal insufficiency  is expected. [ 6 ] [ additional citation(s) needed ]


Oligomeganephronia (or oligomeganephronic hypoplasia) is a rare  pediatric   renal disease  where the number of  nephrons  is reduced but is distinctly enlarged.  Tubules  are also enlarged. This type of  hypoplasia  is more prevalent in  males  with a ratio of three-to-one and is caused by either  renal-coloboma syndrome ,  branchiootorenal syndrome , acro renal syndrome, or  wolf-hirschhorn syndrome . Both  kidneys  are affected symmetrically unless paired with  unilateral agenesis , which is uncommon.  Morphology  is normal. The combined length of both kidneys is 80% or lower than a single normal kidney and the  glomerular filtration rate  is reduced to 30% of the normal. The number of  renal lobes  is reduced to five to six or occasionally as few as one or two. The number of nephrons per lobe is reduced as well.  Malformations  of the urinary tract and  nephrosclerosis  are absent and  vesicoureteral reflux  is insignificant. Unlike  segmental hypoplasia ,  hypertension  is rarely present in this type. The affected are generally born  premature  or small for their  gestational age . Most cases are  sporadic  but some are  inherited . It has been reported that the affected person can have a  twin  or  sibling  with the same condition. In the first few years of the affected individual's life,  dehydration ,  polyuria  and  polydipsia  are present, followed by  hyperfiltration  alongside  proteinuria , with progressive  renal failure  to come after, its onset determined by the combined renal mass. The  end-stage renal disease  occurs between six months and seventeen years. [ 7 ] [ additional citation(s) needed ]