Fetuses [ 1 ]  and newborns [ 2 ]  with Down syndrome without  GATA1  inactivating mutations have numerous hematological abnormalities some of which are similar to those in TMD including increased numbers of circulating  blasts , decreased numbers of circulating platelets and red blood cells, and increased numbers of circulating  white blood cells . Also like TMD, these Down syndrome (no GATA1 mutation) individuals exhibit hepatomegaly, abnormal  liver function tests , and  jaundice . However, these abnormalities are usually more frequent and/or severe in TMD. Furthermore, enlarged spleen, fluid accumulations in body cavities, and  leukemia cutis  (i.e. a rash due to the infiltration of platelet precursor cells into the skin) occur in ~30, 9, and 5%, respectively, of TMD cases but are rarely observed in individuals with Down syndrome (no  GATA1  mutation). The blood of individuals with TMD may contain grossly malformed blast cells, giant platelets, and fragments of megakaryocytes which are rarely seen in individuals with Down syndrome (no  GATA1  mutation).  Bone marrow examination  reveals increases in blast cells in essentially all cases of TMED, increased fibrosis in a small but significant percentage of cases, defective maturation of platelet precursors in ~75% of cases, and defective maturation of red blood cell precursors in 25% of cases. These abnormalities are generally more extreme that those seen in Down syndrome (no  GATA1  mutation). The overall constellation of abnormalities found in TMD often suggest its diagnosis. [ 5 ]


In all individuals suspected of having the symptomatic or silent disease, the diagnosis of TMD requires demonstrating the presence, in the platelet precursor cells of blood, bone marrow, or liver, of  GATA1  mutations that are projected to cause the gene to make GATA1-S but not GATA1 transcription factors. Since these mutations are limited to a clone(s) of platelet precursor cells which may represent only a small fraction of all platelet precursor cells,  high-throughput DNA sequencing methods  are required to detect many cases of the disease, particularly in silent TAM cases which may have only a small number of platelet precursors with the mutation. [ 2 ]  The in utero diagnosis of fetal TMD depends on  medical ultrasound  scanning to detect fluid accumulations in body cavities, cardiac abnormalities (particularly  atrial septal defects ), organ enlargements (particularly of the liver, spleen, or heart), fetal size, and fetal movements. Blood samples are obtained from the fetal  umbilical cord  to determine blood cell counts, measure blood enzymes to evaluate liver function, and the presence in circulating platelet precursor cells of  GATA1  mutations that are associated with TMD. [ 1 ]


Since 80 to 90% of newborns with transient myeloproliferative disease recover within ~3 months (organ enlargement make take longer to resolve), treatment is generally restricted to cases with life-threatening complications. These complications include severe:  a)   hydrops fetalis ;  b)  increases in circulating white blood cells (e.g. >10-fold elevations) that can lead to a blood disorder termed the  hyperviscosity syndrome ;  c)  bleeding due to  disseminated intravascular coagulation  or, less commonly, reduced levels of circulating platelet;  d)  liver dysfunction; or  e)  cardiac dysfunction. There have been no large controlled studies published on treatment but several small studies report that low dose  cytarabine , a  chemotherapeutic drug , has beneficial effects in these cases. High dose cytarabine, however, has been found to be highly toxic in infants with TMD; it is recommended that these dosages be avoided in TMD. The goal of low dose cytarabine in TMD is to reduce the load but not eradicate platelet precursors in tissues and/or circulating megakaryoblasts or, in cases of extreme leukocytosis, white blood cells, particularly since none of these cells are malignant. [ 2 ] [ 5 ]  There is insufficient data to indicate the value of therapy in prenatal cases. Supportive fetal therapy consisting of repeated in utero transfusion of packed red blood cells and platelet concentrates has been reported to reduce the proportion of circulating blast cell, reduce fluid accumulations in fetal cavities, and reduce the size of an  enlarged liver; preterm induction of delivery has also been used in infants with fetal distress. However, further studies are required to determine the clinical usefulness of these and other interventions in prenatal TMD. The  Cochrane Organization  rated the quality of evidence for these fetal interventions as very low. [ 1 ]


Experts suggest that individuals with symptomatic or silent TMD be followed medically for signs and/or symptoms of the disease's progression to AMKL. This includes physical examinations to measure liver and spleen size as well as  complete blood counts  to measure the levels of circulating platelets, erythrocytes, white blood cells, and platelet precursor cells. Recommendations for the frequency of these measurements vary from every 3 to 12 months. [ 2 ]  A complex drug regimen that includes high dose cytarabine [ 20 ]  has shown good  results in treating AMKL. [ 2 ]


Overall mortality during the first year as reported in three studies (all of which included individuals treated for their TMD), range between 15 and 21% in TMD and between 4 and 12% in Down syndrome (no  GATA1  mutation). Virtually all of the deaths occurring in TMD happened within the first 6 months. Risk factors that increased mortality in TMD were prematurity, extremely elevated circulating blast and/or white blood cells, hepatic dysfunction,  ascites  (i.e. fluid in the abdominal cavity), excessive bleeding and/or blood clotting, and kidney dysfunction. [ 5 ]  About 10% of all TMD cases, including those with silent disease, will progress to AMKL at some time during the first 5 years after birth. AMKL associated with Down syndrome is far less severe a disease that AMKL not associated with the syndrome. Event free survival and overall survival (studies include chemotherapy-treated cases) during the 5 years following its diagnosis in Down syndrome children with AMKL is ~80%; it is 43% and 49%, respectively, in children with AMKL who do not have Down syndrome. Median survival in adult AMKL is only 10.4 months. [ 4 ]


TMD was first described and termed congenial leukemia by Bernard and colleagues in a 1951 publication. [ 21 ]  It was defined to be limited to individuals with Down Syndrome and to be spontaneously regressing in 1954, [ 22 ]  and thereafter reported to progress to a leukemia in two reports, the first published in 1957 [ 23 ]  and the second published in 1964. [ 24 ]  Respective reports by D. Lewis in 1981 [ 25 ]  and Bennett  et al  in 1985 [ 26 ]  indicated that the blast cells involved in TMD and its leukemic sequel were platelet precursor cells. Studies by J.D. Crispino and colleagues in 2002 [ 27 ]  and 2003 [ 28 ]  showed that  GATA1  mutations were respectively involved in TMD and AMKL.


Transposition  is a group of  congenital defects  involving an abnormal spatial arrangement of  tissue  or  organ .


Trichothiodystrophy  ( TTD ) is an  autosomal recessive  inherited disorder characterised by brittle hair and intellectual impairment. The word breaks down into  tricho  – "hair",  thio  – "sulphur", and  dystrophy  – "wasting away" or literally "bad nourishment". TTD is associated with a range of symptoms connected with organs of the  ectoderm  and  neuroectoderm . TTD may be subclassified into four syndromes: Approximately half of all patients with trichothiodystrophy have  photosensitivity , which divides the classification into syndromes with or without  photosensitivity ; BIDS and PBIDS, and IBIDS and PIBIDS. Modern covering usage is TTD-P (photosensitive), and TTD. [ 2 ]


Features of TTD can include photosensitivity, ichthyosis, brittle hair and nails,  intellectual impairment, decreased fertility and short stature. A more subtle feature associated with this syndrome is a "tiger tail" banding pattern in hair shafts, seen in microscopy under polarized light. [ 3 ]  The acronyms PIBIDS, IBIDS, BIDS and PBIDS give the initials of the words involved. BIDS syndrome, also called Amish brittle hair brain syndrome and hair-brain syndrome, [ 4 ]  is an  autosomal   recessive [ 5 ]  inherited disease. It is nonphotosensitive. BIDS is characterized by brittle hair, intellectual impairment, decreased fertility, and short stature. [ 6 ] : 501   There is a photosensitive syndrome, PBIDS. [ 7 ]


BIDS is associated with the gene  MPLKIP  (TTDN1). [ 8 ]  IBIDS syndrome, following the acronym from ichthyosis, brittle hair and nails, intellectual impairment and short stature, is the  Tay syndrome  or sulfur-deficient brittle hair syndrome, first described by Tay in 1971. [ 9 ]  (Chong Hai Tay was the Singaporean doctor who was the first doctor in South East Asia to have a disease named after him. [ citation needed ] ) Tay syndrome should not be confused with the  Tay–Sachs disease . [ 6 ] : 485  [ 10 ] [ 11 ] [ 12 ]   It is an  autosomal   recessive [ 13 ]   congenital  disease. [ 6 ] : 501  [ 14 ]  In some cases, it can be diagnosed prenatally. [ 15 ]  IBIDS syndrome is nonphotosensitive.


The photosensitive form is referred to as PIBIDS, and is associated with  ERCC2/XPD [ 10 ]  and  ERCC3 . [ 16 ]


All photosensitive TTD syndromes have defects in the  nucleotide excision repair  (NER) pathway, which is a vital DNA repair system that removes many kinds of DNA lesions. This defect is not present in the nonphotosensitive TTD's. [ 17 ]  These type of defects can result in other rare autosomal recessive diseases like  xeroderma pigmentosum  and  Cockayne syndrome . [ 18 ]


Currently, mutations in four genes are recognized as causing the TTD phenotype, namely  TTDN1 ,  ERCC3/XPB ,  ERCC2/XPD  and  TTDA . [ 19 ]   Individuals with defects in  XPB ,  XPD  and  TTDA  are photosensitive, whereas those with a defect in  TTDN1  are not.  The three genes,  XPB ,  XPD  and  TTDA , encode protein components of the multi-subunit  transcription/repair factor IIH  (TFIIH).  This complex factor is an important decision maker in  NER  that opens the  DNA  double helix after damage is initially recognized.  NER is a multi-step pathway that removes a variety of different DNA damages that alter normal base pairing, including both UV-induced damages and bulky chemical adducts.  Features of premature aging often occur in individuals with mutational defects in genes specifying protein components of the NER pathway, including those with TTD [ 20 ]  (see  DNA damage theory of aging ).


Triphalangeal thumb  ( TPT ) is a  congenital  malformation where the  thumb  has three  phalanges  instead of two. The extra phalangeal bone can vary in size from that of a small pebble to a size comparable to the phalanges in non-thumb digits. The true  incidence  of the condition is unknown, but is estimated at 1:25,000 live births. [ 1 ]  In about two-thirds of the patients with triphalangeal thumbs, there is a hereditary component. [ 2 ]  Besides the three phalanges, there can also be other malformations. It was first described by Columbi in 1559. [ 3 ]


The triphalangeal thumb has a different appearance than normal thumbs. The appearance can differ widely; the thumb can be a longer thumb, it can be deviated in the radio-ulnar plane ( clinodactyly ), or thumb strength can be diminished. In the case of a five-fingered hand it has a finger-like appearance, with the position in the plane of the four fingers,  thenar muscle  deficiency, and additional length. There is often a combination with radial  polydactyly .


Generally, triphalangeal thumbs are non-opposable. In contrast to most people with  opposable thumbs , a person suffering from TPT cannot easily place his or her thumb opposite the other four digits of the same hand. The opposable thumb's ability to effortlessly utilize fingers in a "pinch" formation is critical in precision gripping. For the thumb to adequately grip, certain thumb criteria must be met (e.g. suitable position and length, stable  joints  and good  thenar muscle  strength). [ 4 ]  Because triphalangeal thumbs cannot easily oppose and do not possess many of the optimal qualities found in most opposable thumbs, they tend to cause the hand to be less effective in use and, therefore, prove to be more problematic in daily life.


Malformations of the upper extremities can occur in the third to seventh embryonic week. [ 5 ]  In some cases the TPT is hereditary. In these cases, there is a mutation on  chromosome 7q 36. [ 6 ]  If the TPT is hereditary, it is mostly inherited as an autosomal dominant trait, [ 7 ]  non-opposable and bilateral. [ 2 ]  The sporadic cases are mostly opposable and unilateral. [ 8 ]


Triphalangeal thumb can occur in syndromes but it can also be isolated. The triphalangeal thumb can appear in combination with other malformations or syndromes. [ 5 ]


Syndromes include:


Malformations include: [ 5 ]


There are multiple classifications for the triphalangeal thumb. The reason for these different classifications is the heterogeneity in appearance of the TPT.
The classification according to Wood  [ 9 ]  describes the shape of the extra phalanx: delta (Fig. 4), rectangular or full phalanx (Table 1). With the classification made by Buck-Gramcko a surgical treatment can be chosen (Table 1). Buck-Gramcko differentiates between six different shapes of the extra phalanx and associated malformations. [ 10 ]


Table 1 : Classifications of Wood  [ 9 ]  and Buck-Gramcko  [ 10 ]


The goals of surgical treatment are: reducing length of the thumb, creating a good functioning, a stable and non-deviated joint and improving the position of the thumb if necessary. Hereby improving function of the hand and thumb.


In general the surgical treatment is done for improvement of the thumb function. However, an extra advantage of the surgery is the improvement in appearance of the thumb. In the past, surgical treatment of the triphalangeal thumb was not indicated, [ 11 ]  but now it is generally agreed that operative treatment improves function and appearance. Because an operation was not indicated in the past, there's still a population with an untreated triphalangeal thumb. The majority of this population doesn't want surgery, because the daily functioning of the hand is good. [ 11 ]  The main obstacle for the untreated patients might not be the diminished function, but the appearance of the triphalangeal thumb. [ 11 ]
The timing of surgery differs between Wood and Buck-Gramcko. Wood advises operation between the age of six months and two years, [ 12 ]  while Buck-Gramcko advises to operate for all indications before the age of six years. [ 13 ]


Triple-A syndrome  or  AAA syndrome  is a rare  autosomal   recessive   congenital disorder . In most cases, there is no family history of AAA syndrome. [ 2 ]   The syndrome was first identified by  Jeremy Allgrove  and colleagues in 1978; since then just over 100 cases have been reported. [ 3 ]  The syndrome is called Triple-A due to the manifestation of the illness which includes  achalasia  (a dysfunction of the esophagus),  addisonianism  ( adrenal insufficiency  of primary type), and  alacrima  (insufficiency of  tears ). Alacrima is usually the earliest manifestation. [ 4 ]  Neurodegeneration or atrophy of the nerve cells and autonomic dysfunction may  be seen in the disorder; therefore, some have suggested the disorder be called 4A syndrome. [ 5 ]  It is a progressive disorder that can take years to develop the full-blown clinical picture. [ 6 ]  The disorder also has variability and heterogeneity in presentation. [ 7 ]


Individuals affected by AAA have  adrenal insufficiency / Addison's disease  due to ACTH resistance, alacrima (absence of tear secretion), and  achalasia  (a failure of a ring of muscle fibers in the lower part of the esophagus to relax) called the lower  esophageal sphincter  at the  cardia  (very upper portion of the stomach). The esophagus is the tube that carries food from the mouth to the stomach.  Achalasia delays food going to the stomach and causes dilation of the thoracic esophagus. There may also be signs of autonomic dysfunction, such as pupillary abnormalities, an abnormal reaction to intradermal histamine, abnormal sweating, orthostatic hypotension (low blood pressure with standing), and disturbances of the heart rate. [ 8 ]  Unexplained  hypoglycemia  (low blood sugar) is often mentioned as an early sign. [ 6 ]  The disorder has also been associated with mild  intellectual disability . [ 6 ]  The syndrome is highly variable. However, one of the most common findings in all patients are the lack of tears. Lack of tears with crying is often mentioned in hindsight after the diagnosis has been made. [ 7 ]  AAA syndrome may be diagnosed in early childhood or in adolescence. The disorder is typically managed by treating the symptoms with hormone replacement for adrenal insufficiency, lubricating drops for the eyes and managing low blood sugars. [ 9 ]


Triple-A syndrome is associated with mutations in the  AAAS  gene which encodes a protein known as  ALADIN  (ALacrima Achalasia adrenal Insufficiency Neurologic disorder). [ 10 ] [ 11 ] [ 12 ]  In 2000, Huebner  et al.  mapped the syndrome to a 6 cM interval on human chromosome 12q13 near the type II keratin gene cluster. [ 13 ]  Since inheritance and gene for the association is known, early diagnosis can allow genetic counseling. [ 4 ]  Furthermore, genotypic heterogeneity has also been documented suggesting that there may be other genes involved in this genetic disorder as well as unknown environmental factors that result in the phenotypic expression of the disease. [ 7 ]


ALADIN protein is a component of the  nuclear pore complex , situated toward its cytoplasmic side.  Mutant ALADIN remains mis-localized in the cytoplasm [ 14 ]  and causes selective failure of  nuclear protein import  and hypersensitivity to  oxidative stress . [ 15 ]   Mutant ALADIN also causes decreased nuclear import of  aprataxin , a  repair protein for DNA single-strand breaks , and DNA  ligase I . [ 15 ]   These decreases in DNA repair proteins may allow accumulation of  DNA damage  that trigger cell death. [ 7 ]


Nucleoporin  ALADIN participates in spindle assembly. ALADIN is employed in specific  meiotic stages , including spindle assembly, and spindle positioning. [ 16 ]  Female mice homozygously null for ALADIN are sterile. [ 16 ]


The diagnosis of this condition involves examination by a health provider. Clinical signs may lead to the diagnosis such as the lack of tears and digestive issues, such as acid reflux disease in infancy as well as symptoms of adrenal insufficiency such as frequent bouts of low blood sugars are highly suggestive of the disorder. [ 7 ] [ 5 ] [ 9 ]  Achalasia may be seen on plain X-rays and include an absence of fundal gas shadow, widened mediastinum and an air fluid level in mediastinum is also seen. The gold standard for confirming achalasia is a 24 hours manometry of oesophagus.This is a test that measures the pressure inside the esophagus. The test demonstrates non-relaxation of lower esophageal sphincter, increased tone of esophageal sphincter, atonic esophagus. Bird-beak sign and rat-tail sign can be appreciated on barium swallow. [ 17 ] [ 18 ] [ 19 ]  Lack of tears or alacrima is caused by the lack of production of lacrimal glands or ducts and defects in the nerves of the lacrimal gland caused by a dysfunction in the autonomic nervous system. [ 20 ]  The diagnosis is confirmed with  genetic testing  as well as clinical features. [ 9 ]


There is no definitive cure for this syndrome because many of the mechanisms implicated have not yet been identified. The available treatments address only some of the symptoms. Lubricating drops and emulsions are used to remedy the absence of tear secretion.  Achalasia can be treated with surgical intervention resulting in improved passage of food and drink into the stomach.  Corticosteroids, such as hydrocortisone, are prescribed to solve the adrenal insufficiency. [ 21 ]  Early diagnosis may prevent morbidity and improve growth in children due to early treatment of adrenal insufficiency. [ 9 ]


Triploid syndrome , also called  triploidy , is a  chromosomal disorder  in which a fetus has three copies of every  chromosome  instead of the normal two. If this occurs in only some cells, it is called  mosaic  triploidy and is less severe.


Most embryos with triploidy  miscarry  early in development.


Many organ systems are affected by triploidy, but the  central nervous system  and skeleton are the most severely affected:


Common central nervous system defects seen in triploidy include  holoprosencephaly ,  hydrocephalus  (increased amount of cerebrospinal fluid within the brain),  ventriculomegaly ,  Arnold–Chiari malformation ,  agenesis of the corpus callosum  and  neural tube defects . [ citation needed ]


Skeletal manifestations include  cleft lip/palate ,  hypertelorism ,  club foot  and  syndactyly  of fingers three and four [ citation needed ] .


Congenital heart defects ,  hydronephrosis ,  omphalocele  and meningocele ( spina bifida ) are also common.  Cystic hygromas  occur but are uncommon. [ citation needed ]


Triploid fetuses have  intrauterine growth restriction  beginning early in the pregnancy, as early as 12 weeks, and does not affect the head as severely as the body.  Oligohydramnios , low levels of amniotic fluid, is common in triploid pregnancies. Placental abnormalities are common in triploidy. Most frequently, the placenta is enlarged and may have cysts within. In some cases, the placenta may be unusually small, having ceased to grow. [ 2 ]


During the first trimester, fetuses with triploidy have a thicker  fluid under the skin behind their neck , which calls for observation during the first and second trimester of gestation. [ citation needed ]


The mother will usually have high levels of specific proteins including  maternal serum alpha-fetoprotein  (AFP) and  beta-human chorionic gonadotropin  (hCG). Symptoms may include, but are not limited to, swelling,  edema , or  hypertension . [ medical citation needed ]


Infants may show facial abnormalities,  micrognathia ,  cleft lip ,  spina bifida , as well as other birth defects that result from kidney, limb, and umbilical cord complications. They are also prone to being  smaller than a normal sized newborn , a problem that arises while the infant is still a fetus. [ citation needed ]


Triploidy is caused by an extra set of chromosomes. [ citation needed ]


Triploidy can result from either two  sperm  fertilizing one  egg  ( polyspermy ) (60%) or from one sperm fertilizing an egg with two  copies of every chromosome  (40%). [ 2 ]  These are otherwise known as diandric fertilization and digynic fertilization. Pregnancies caused by digynic fertilization are more likely to end right before a baby is due for full term. Pregnancies caused by diandric fertilization result in a miscarriage towards the first trimester. [ medical citation needed ]


Another factor known as a  partial mole pregnancy  can cause triploidy. It is known to cause early termination, cancer, and even a second molar pregnancy. [ medical citation needed ]


Triploidy may be suggested by dramatically elevated levels of  serum alpha-fetoprotein . On  obstetric ultrasonography , abnormalities of the skeleton, central nervous system, heart, abdomen, and kidneys are visible in the most severe cases beginning at 12-14 weeks of pregnancy. Placental abnormalities associated with a triploid pregnancy become visible at 12-14 weeks.  Placentomegaly  or intrauterine growth restriction are the typical findings that prompt evaluation for triploidy, though oligohydramnios may be the first sign in some cases. Placentomegaly is not pathognomonic for triploidy because in some cases, the placenta senesces. [ 2 ]


Triploidy must be distinguished from  trisomy 13  and  trisomy 18 , which may appear similar on sonography.  Genetic testing  allows for a definitive diagnosis. [ 2 ]


A  sample of amniotic fluid  can also be tested to diagnose triploidy. [ medical citation needed ]


Most fetuses with triploidy do not survive to birth, and those that do usually die within days. As there is no treatment for triploidy,  palliative care  is given if a baby survives to birth. If triploidy is diagnosed during the pregnancy, termination is often offered as an option due to the additional health risks for the mother ( pre-eclampsia , a life-threatening condition, or  choriocarcinoma , a type of cancer). Should a mother decide to carry until term or until a spontaneous miscarriage occurs, doctors will monitor her closely in case either condition develops. [ citation needed ]


Mosaic  triploidy has an improved prognosis, but affected individuals have moderate to severe  cognitive disabilities . [ 2 ]


Triploidy affects approximately 1–2% of pregnancies, but most  miscarry  early in development. At birth, males with triploidy are 1.5 times more common than females. [ 2 ]


Tyrosine hydroxylase deficiency  (THD) is a disorder caused by disfunction of  tyrosine hydroxylase , an enzyme involved in the biosynthesis of  dopamine . This condition is one of the causes of  dopa-responsive dystonia . [ 2 ]


Patients present with symptoms reflecting the decreased production of  dopamine : hypokinetic-rigid syndrome,  dystonia , complex encephalopathy. Symptom severity and age at onset are highly variable. A review published on  GeneReviews  and last updated in 2017 suggests the approximate subdivision of patients into three groups based on differences in severity of symptoms, nature of symptoms, and age at onset. [ 3 ]  A review published more recently, in 2021, suggests that the disease may have a more gradual and overlapping spectrum, and categorization may be imprecise. [ 1 ]


According to the classification on GeneReviews, [ 3 ]  three approximate phenotypes could be discerned:


In order to diagnose tyrosine hydroxylase deficiency, a sample of the patient's  cerebrospinal fluid  may be obtained to assess neurotransmitter metabolites that may be affected, as illustrated by the metabolic links in Figure 1. Patients typically have normal levels of  5-hydroxyindolacetic acid  (5HIAA), low levels of  homovanillic acid  (HVA) and  3-methoxy-4-hydroxyphenylethylene glycol  (MHPG), and a low HVA:5-HIAA ratio. [ 1 ]  Upon finding a pattern of CSF abrormalities suggestive of the disease, the diagnosis may be confirmed by analysing the  TH  gene encoding the enzyme. [ 1 ]


According to a review of dopa-responsive dystonias published in 2021, tyrosine hydroxylase deficiency may be hard to diagnose, with a median diagnostic delay of 4 years, [ 2 ]  and misdiagnosis happens in a significant proportion of patients, with  cerebral palsy  being the most common erroneous diagnosis. [ 2 ]


Patients with tyrosine hydroxylase deficiency are treated with  L-dopa  in conjunction with  decarboxylase inhibitors . A significant percentage of patients do not achieve a complete response on this regimen. [ 1 ]


The first case reports of "Segawa syndrome" and  parkinsonism  caused by mutations in the tyrosine hydroxylase gene were published in 1995 [ 1 ] [ 4 ]  and 1996. [ 5 ] [ 6 ]


The  Ulas family  of 19 is from rural southern  Turkey . Five of the  family  members (except for another, who has died) walk on all fours with their feet and the palms of their  hands  in what is called a "bear crawl". [ 1 ] [ 2 ]  Their quadrupedal  gait  has never been reported in  anatomically  intact  adult  humans. The gait is different from the  knuckle-walking  quadrupedal gait of  apes . In 2006, the family was the subject of a  documentary :  The Family That Walks On All Fours .


The affected people have a form of  non-progressive congenital cerebellar ataxia . The brain impairments include  cerebellar hypoplasia , mild  cerebral cortex   atrophy  and a reduced  corpus callosum . They are also mildly  intellectually disabled  and have problems in  balancing  on two  legs . However, they do not show the poor coordination of  hands ,  speech , and  eye  movements often found in  cerebellar ataxia . The four sisters can do  needlework . They all share a  recessive   mutation  on  chromosome 17p . [ 3 ]


Üner Tan  of  Çukurova University  Medical School in  Adana , has said that they show characteristics of the  primate  ancestors of  Homo sapiens , before the move to  bipedalism . He calls the process "backward evolution" and he named the condition  Uner Tan syndrome . [ 4 ]


However,  Nicholas Humphrey ,  John Skoyles , and  Roger Keynes  have argued that their gait is due to two rare phenomena coming together. [ 5 ]  First, instead of initially  crawling  as  infants  on their  knees , they started off  learning  to move around with a "bear crawl" on their feet. [ 5 ]  Second, due to their  congenital  brain impairment, they found  balancing  on two  legs  difficult. [ 5 ]  Because of this, their  motor development  was channeled into turning their bear crawl into a substitute for bipedality. [ 5 ]


Defne Aruoba is a Turkish psychologist who was involved with the care and research of the Ulas family. Because of her experience working with the Ulas family, she planned to establish the Ulas Foundation, which will bridge the gap between social inequalities and contact other individuals and families in need of rehabilitation. [ 6 ]


Ulnar dimelia , also referred to simply as  mirror hand , is a very rare  congenital disorder  characterized by the absence of the radial ray, duplication of the  ulna , duplication of the  carpal ,  metacarpal , and  phalanx  bones, and symmetric  polydactyly . In some cases surgical  amputation  is performed to remove the duplicate carpals, metacarpals and phalanges. As of 2015, approximately 70 cases have been recorded in the medical literature. [ citation needed ]


The cause is thought to be an error during embryonic development and typically only one arm is affected. [ 1 ]


Bone deformity may also accompany nervous and arterial anomalies in some cases due to the duplication of the  ulnar nerve , the presence of abnormal arterial arches, the duplication of the   ulnar artery , the shortening of the  radial nerve , and the absence of the  radial artery . The diagnosis of ulnar dimelia is based on laboratory tests of frontal and sagittal planes in individuals suspected of the condition. There are two types of ulnar dimelia noted in medical journals: Type 1 ulnar dimelia entails one  lunate  and one  trapezoid bone  as well as one  index finger , while type 2 ulnar dimelia has two lunate and two trapezoid bones as well as two index fingers. [ citation needed ]


The  American Society for Surgery of the Hand  and the International Federation of Societies for Surgery of the Hand classified ulnar dimelia in the third group of congenital hand deformities in accordance with the characteristics proposed in the Swanson classification (1976). [ citation needed ]


Umbilical cord ulceration and intestinal atresia  is a rare [ 1 ]   congenital  disease that leads to  intestinal atresia , umbilical cord ulceration and severe intrauterine  haemorrhage . Only 15 cases have so far been reported, [ 2 ]  though newer studies are beginning to conclude that this disease has a higher incidence rate than has been previously reported. [ 3 ]  A particular study has given intestinal atresia and umbilical cord ulceration a clear link after 5 such cases were reported at the time of publication. [ 4 ]


This article about a disorder arising in the  perinatal  period is a  stub . You can help Wikipedia by  expanding it .


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


Urofacial syndrome , or  Ochoa syndrome , is an  autosomal   recessive [ 1 ]   congenital disorder  characterized by an association of a lower urinary tract and bowel dysfunction with a typical facial expression: when attempting to smile, the patient seems to be crying or grimacing. It was first described by the Colombian physician Bernardo Ochoa in the early 1960s. The inverted facial expression presented by children with this syndrome allows for early detection of the syndrome, which is vital for establishing a better prognosis as urinary related problems associated with this disease can cause harm if left untreated.  Incontinence  is another easily detectable symptom of the syndrome that is due to  detrusor - sphincter  discoordination.


It may be associated with  HPSE2 . [ 2 ]


Infants with the disorder exhibit an inverted smile; they appear to be crying when they are actually smiling, in conjunction with  uropathy . They also may be affected by  hydronephrosis . Symptoms of this disease can start at very young ages. Many people with this syndrome will die in their teens to early 20s because of the renal failure (uropathy) if not diagnosed and treated. Children with the syndrome have abnormal facial development that cause an inverted smile; nerve connections are however normal. When attempting to smile, the child will appear to cry. Urinary problems arise as a result of a  neurogenic bladder . Most patients older than the age of toilet training, present with  enuresis ,  urinary-tract infection ,  hydronephrosis , and a spectrum of radiological abnormalities typical of obstructive or neurogenic bladders. Radiological abnormalities include things such as: trabeculated bladder, vesicoureteral reflex, external sphincter spasm,  pyelonephritis , hyperreflexic bladder, noninhibited  detrusor  contraction, etc. Urinary abnormalities might result in renal deterioration and failure. This can be prevented by taking proper measures to restore normal  micturition  and by taking antibiotics to prevent infections. In some cases, the affected patients become  hypertensive  and progress to end-stage renal disease, while others become  uremic . Additionally, most patients suffer from  constipation . [ 3 ]
Early detection of this syndrome is possible through the peculiar faces that children present. [ citation needed ]


Urofacial syndrome occurs due to either disruption or mutation of a gene on chromosome  10q23q24 . [ 4 ]  The gene is located on a 1  centimorgan  interval between D10S1433 and D10S603. [ 3 ]  Alteration of this gene leads to alteration of facial and urinary developmental fields. This gene is believed to be the  HPSE2  gene. The HPSE2 gene is expressed in both the central nervous system as well as the bladder.  Heparanase 2  is protein coded by exons 8 and 9 on the HPSE2 gene. This protein is believed to be altered in the case of this syndrome. [ 2 ]  Studies performed on mice indicate that HPSE2 has no  enzymatic activity . [ 5 ]


Mutations in the HPSE2 gene on  chromosome  10q23q24 have been observed to cause Ochoa Syndrome. This means the defective gene responsible for the disorder is located on an  autosome  (chromosome 10 is 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 ]


The relationship between a defective HPSE2 gene and Ochoa syndrome is unclear. Early on, there was speculation that the genetic changes may lead to an abnormality in the brain stem. Evidence for this postulation was that the areas of the brain that control facial expression (VII nerve nuclei) and urination (the pontine micturition centre) were believed to be in close proximity of each other. Other hypotheses posit that the defective heparanase 2 protein may lead to problems with development of the  urinary tract  autonomic nervous system, or with muscle function in the face and bladder. [ 6 ]


The treatment varies based on the condition and extent of the  uropathy .
To empty the bladder regularly, clean intermittent catheterization (CIC) can be used. If the urodynamic study shows non-inhibited detrusor contractions, an anticholinergic drug should be given additionally. To prevent recurrent infections, especially in the case of vesicoureteral reflux, the treatment can also include an antibiotic prophylaxis. [ citation needed ]


Urofacial (Ochoa) syndrome received the Ochoa name because of the first person to describe it in 1987, Bernardo Ochoa. [ 3 ]


The  VACTERL association  (also  VATER association , and less accurately  VACTERL syndrome ) refers to a recognized group of  birth defects  which tend to co-occur (see  below ). This pattern is a recognized association, as opposed to a  syndrome , because there is no known pathogenetic cause to explain the grouped incidence.


Each child with this condition can be unique. At present this condition is treated after birth with issues being approached one at a time. Some infants are born with symptoms that cannot be treated and they do not survive. Also, VACTERL association can be linked to other similar conditions such as  Klippel Feil  and  Goldenhar syndrome  including crossovers of conditions.


No specific genetic or chromosome problem has been identified with VACTERL association. VACTERL can be seen with some chromosomal defects such as  Trisomy 18  and is more frequently seen in babies of diabetic mothers. VACTERL association, however, is most likely caused by multiple factors. [ 1 ]


VACTERL association specifically refers to the abnormalities in structures derived from the embryonic  mesoderm .


The following features are observed with VACTERL association: [ 2 ] [ 3 ]


Although it was not conclusive whether VACTERL should be defined by at least two or three component defects, [ 4 ]  it is typically defined by the presence of at least three of the above congenital malformations. [ 5 ]


Vertebral anomalies, or defects of the spinal column, usually consist of small ( hypoplastic ) vertebrae or hemivertebra where only one half of the bone is formed. About 80 percent of patients with VACTERL association will have vertebral anomalies. [ 6 ]  In early life these rarely cause any difficulties, although the presence of these defects on a chest x-ray may alert the physician to other defects associated with VACTERL. Later in life these spinal column abnormalities may put the child at risk for developing  scoliosis , or curvature of the spine. [ 5 ]


Anal atresia  or imperforate anus is seen in about 55 to 90 percent of patients with VACTERL association. These anomalies are usually noted at birth. [ 7 ]  It often require surgery in the first days of life. Sometimes babies will require several surgeries to fully reconstruct the intestine and anal canal. [ 5 ]


Approximately 40-80 percent of patients with VACTERL association have been reported to have  congenital heart disease . [ 5 ]  The most common heart defects seen with VACTERL association are  ventricular septal defect  (VSD),  atrial septal defects  and  tetralogy of Fallot .
Less common defects are  truncus arteriosus  and  transposition of the great arteries . It is subsequently thought that cardiac defects should be considered an  extension  of VACTERL. [ 4 ]


Esophageal atresia  with  tracheoesophageal fistula  (TO fistula or TOF) is seen in about 70 percent of patients with VACTERL association, although it can frequently occur as an isolated defect. 15 to 33 percent of patients with TO fistulas will also have congenital heart disease. However these babies usually have uncomplicated heart defects, like a  ventricular septal defect , which may not require any surgery. [ citation needed ]


Kidney defects are seen in approximately 50 percent of patients with VACTERL association. In addition, up to 35 percent of patients with VACTERL association have a  single umbilical artery  (there are usually two arteries and one vein) which is often associated with additional kidney or urologic problems. Renal abnormalities in VACTERL association can be severe, with  incomplete formation of one or both kidneys  or urologic abnormalities such as obstruction of outflow of urine from the kidneys or severe reflux (backflow) of urine into the kidneys from the bladder. These problems can cause  kidney failure  early in life and may require  kidney transplant . Many of these problems can be corrected surgically before any damage can occur. [ citation needed ]


Limb defects occur in up to 70 percent of babies with VACTERL association and include a displaced or  hypoplastic thumb , extra digits ( polydactyly ), fusion of digits ( syndactyly ) and forearm defects such as  radial aplasia . Babies with limb defects on both sides tend to have kidney or urologic defects on both sides, while babies with limb defects on only one side of the body tend to have kidney problems on that same side. [ citation needed ]


Features secondary to VACTERL components are frequent enough to be considered an extension of VACTERL. These include:  single umbilical artery ,  ambiguous genitalia ,  abdominal wall defects ,  diaphragmatic hernia , intestinal and respiratory anomalies, and  oligohydramnios  sequence defects. [ 4 ] [ 8 ]   Cardiac defects are thought to fit in this category. [ 4 ]


Many babies with VACTERL are born small and have difficulty with gaining weight. Babies with VACTERL association, however, do tend to have normal development and normal intelligence. [ citation needed ]


Patients with abnormal cardiac and kidney function may be more at risk for  hemolytic uremic syndrome .


The incidence of VACTERL association is estimated to be approximately 1 in 10,000 to 1 in 40,000 live-born infants. [ 5 ]  It is seen more frequently in infants born to  diabetic  mothers. While most cases are sporadic, there are clearly families who present with multiple involved members. [ citation needed ]


The acronym  VATER  association was first described by Linda Quan, an emergency room physician, and David Smith, a man who was considered the father of  dysmorphology  in 1972, to define a non-random co-occurrence of the listed defects. Years later, research revealed that cardiac and renal abnormalities were common in the association, and the acronym was changed to  VACTERL . [ 10 ]  However, no single cause was identified that links all these conditions together. Therefore, this VACTERL is termed as "association" instead of a "syndrome".


The differentiation of the acronyms VACTERL and VATER is due to the variation in defects determined at or prior to birth. VACTERL contains vertebral, anal, cardiac, trachea-esophageal, renal/kidney, and limb defects where as VATER only has vertebral, anal, trachea-esophageal, and renal defects. The "R" in VATER represented radial dysplasia.  Though the differences are clear, the physical defects vary from case to case. [ citation needed ]


A  vaginal septum  is a  vaginal anomaly  that is partition within the  vagina ; such a  septum  could be either longitudinal or transverse. In some affected women, the septum is partial or does not extend the length or width of the vagina. [ 1 ]   Pain during intercourse  can be a symptom. A longitudinal vaginal septum develops during  embryogenesis  when there is an incomplete fusion of the lower parts of the two  Müllerian ducts . As a result, there may appear to be two openings to the vagina. There may be associated duplications of the more cranial parts of the Müllerian derivatives, a double  cervix , and either a  uterine septum  or  uterus didelphys  (double uterus). [ 1 ] [ 2 ]  A transverse septum forms during embryogenesis when the Müllerian ducts do not fuse to the  urogenital sinus . A complete transverse septum can occur across the vagina at different levels. Menstrual flow can be blocked, [ 3 ]  and is a cause of primary  amenorrhea . The accumulation of menstrual debris behind the septum is termed  cryptomenorrhea . Some transverse septa are incomplete and may lead to  dyspareunia  or obstruction in  labour . [ 4 ] [ 5 ]


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Van der Woude syndrome  (VDWS) is a  genetic disorder  characterized by the combination of lower  lip pits , cleft lip with or without cleft palate (CL/P), and cleft palate only (CPO). [ 1 ]  The frequency of orofacial clefts ranges from 1:1000 to 1:500 births worldwide, and there are more than 400 syndromes that involve CL/P. [ 2 ]   VWS is distinct from other clefting syndromes due to the combination of  cleft lip and palate  (CLP) and CPO within the same family.  Other features frequently associated with VWS include  hypodontia  in 10-81% of cases, narrow arched palate, congenital heart disease, heart murmur and cerebral abnormalities,  syndactyly  of the hands, polythelia,  ankyloglossia , and adhesions between the upper and lower gum pads. [ 3 ]


The association between lower lip pits and cleft lip and/or palate was first described by Anne Van der Woude in 1954.  The worldwide disease incidence ranges from 1:100,000 to 1:40,000. [ 4 ]


Van der Woude syndrome is inherited as an autosomal dominant disease caused by a mutation in a single gene with equal distribution between the sexes.  The disease has high penetrance at about 96% but the phenotypic expression varies from lower lip pits with cleft lip and cleft palate to no visible abnormalities. [ 2 ] [ 4 ]  Approximately 88% of VWS patients display lower lip pits, and in about 64% of cases lip pits are the only visible defect.  Reported clefting covers a wide range including submucous cleft palate, incomplete unilateral CL, bifid uvula, and complete bilateral CLP.  VWS is the most common orofacial clefting syndrome, accounting for 2% of CLP cases. [ 3 ]


The majority of VWS cases are caused by  haploinsufficiency  due to mutations in the interferon regulatory factor 6 gene ( IRF6 ) on chromosome 1 in the 1q32-q41 region known as VWS locus 1.  A second, less common, causative locus is found at 1p34, known as VWS locus 2 (VWS2). More recent work has shown that GRHL3 is the VWS2 gene.  Grhl3  is downstream of  Irf6  in oral epithelium, suggesting a common molecular pathway leading to VWS. Prior work also suggested  WDR65  as a candidate gene. [ 4 ] [ 5 ]   IRF6  contains two non-coding and seven coding exons and is part of a family of nine transcription factors with a highly conserved helix-turn-helix DNA binding domain called the Smad-interferon regulatory factor binding domain (SMIR).  Mutations in coding or non-coding  IRF6  exons can result in Van der Woude syndrome. [ 2 ]  Due to the wide range of expressivity, it is also believed that other unidentified loci contribute to disease development. [ 4 ]


An example of the clear phenotypic variability is a monozygotic twin study conducted by Jobling et al. (2010).  Two monozygotic female twins had the same  IRF6  mutation; however Twin A was born with a bilateral cleft lip, whereas Twin B had bilateral lip pits and no orofacial clefting.  Both twins were diagnosed with VWS.  The twins' father had lip pits alone and a family history of CLP, CP, CL, and/or lip pits.  Both twins were diagnosed with VWS.   Polymerase chain reaction  (PCR) amplification was done for all exons of  IRF6 , and a  missense mutation  was discovered in exon 4.  The tyrosine in the normal protein at this position is conserved across mammals, frogs, and chickens, so despite the fact that it was a previously unreported mutation, it was expected to be deleterious.  This study is not the first case of different phenotypes occurring between monozygotic twins.  Possible causes of phenotypic variability include variations in the intrauterine environment, epigenetic differences, or chance effects. [ 6 ]


Lip pits were first reported in 1845 by Demarquay who thought they were indentations made by the upper incisors.  Today it is known that they occur during  embryogenesis  due to  IRF6  mutations.  On day 32 of embryonic development there are four growth centers of the lower lip divided by two lateral grooves and one median.  By day 38 of normal development, the grooves have disappeared.  However, when growth of the mandibular process is impeded, a lip pit occurs.  Lip pits begin to develop on day 36.  Cleft lip begins to develop on day 40, and cleft palate emerges on day 50 of development. [ 3 ]


There are three types of lip pits, which are classified according to their location: midline upper, comissural, and lower lip.  The most common phenotype is two symmetrical lower lip pits flanking both sides of the midline in the bilateral paramedial sinuses.  Lower lip pits may also be bilaterally, unilaterally, or medially asymmetrical.  The occurrence of a single lip pit is considered incomplete expression, and it typically occurs on the left side of the lower lip.  There are also three different shapes for lip pits, the most common being circular or oval; less common forms include slit-like or transverse.  The lip pits extend into the  orbicularis oris muscle , ending in blind sacs surrounded by mucous glands.  In some cases mucus is excreted when the muscles contract. [ 3 ]


Clinical diagnosis based on orofacial clefts and lip pits typically occurs shortly after birth.  Certain defects may be difficult to diagnose, particularly a submucous cleft palate.  This form of CP may not be detected except through finger palpation, as the  mucosa  covering the palate is intact, but the muscles underneath have lost their proper attachments.  Feeding problems, impaired speech, and hearing loss are symptoms of a submucous cleft palate. [ 4 ]  Furthermore, approximately 15% of VWS cases with orofacial clefts, in the absence of prominent lip pits, cannot be easily distinguished from non-syndromic forms of orofacial clefting. [ 7 ]   Therefore, it is very important to closely examine these patients as well as their relatives for lip pits, especially when there is a family history of mixed clefting, in order to make the VWS diagnosis. [ 3 ]  Dentists may also play an important role in diagnosing cases not detected at birth, as they detect hypodontia commonly associated with VWS.  The
patients most commonly lack the upper second premolars followed by the lower second premolars and upper lateral incisors.  The absence of these teeth might play a role in the constricting of the dental arches. [ 3 ] [ 4 ]


The clinical signs seen in VWS are similar to those of  popliteal pterygium syndrome  (PPS), which is also an autosomal dominant disease.  Approximately 46% of affected individuals have lip pits; other features include genital abnormalities, abnormal skin near nails, syndactyly of fingers and toes, and webbed skin.  The disease is also caused by mutations in  IRF6 ; however, they occur in the DNA-binding domain of  IRF6  and result in a dominant negative effect in which the mutated IRF6 transcription factor interferes with the ability of the  wild type  copy to function, in the case of a heterozygous individual. [ 2 ]


Genetic counseling for VWS involves discussion of disease transmission in the autosomal dominant manner and possibilities for penetrance and expression in offspring. [ 3 ]   Autosomal dominance means affected parents have a 50% chance of passing on their mutated  IRF6   allele  to a their child.  Furthermore, if a cleft patient has lip pits, he or she has a ten times greater risk of having a child with cleft lip with or without cleft palate than a cleft patient who does not have lip pits. [ 4 ]   Types of clefting between parents and affected children are significantly associated; however, different types of clefts may occur horizontally and vertically within the same pedigree.  In cases where clefting is the only symptom, a complete family history must be taken to ensure the patient does not have non-syndromic clefting. [ 3 ]


Lip pits may be surgically removed either for aesthetic reasons or discomfort due to inflammation caused by bacterial infections or chronic saliva excretion, though spontaneous shrinkage of the lip pits has occurred in some rare cases.  Chronic inflammation has also been reported to cause  squamous-cell carcinoma .  It is essential to completely remove the entire lip pit canal, as mucoid cysts can develop if mucous glands are not removed.  A possible side effect of removing the lip pits is a loose lip muscle.  Other conditions associated with VWS, including CL, CP, congenital heart defects, etc. are surgically corrected or otherwise treated as they would be if they were non-syndromic. [ 3 ]


Velopharyngeal inadequacy  is a malfunction of a velopharyngeal mechanism which is responsible for directing the transmission of  sound energy  and  air pressure  in both the  oral cavity  and the  nasal cavity . When this mechanism is impaired in some way, the  valve  does not fully close, and a condition known as "velopharyngeal inadequacy" can develop. VPI can either be  congenital  or acquired later in life.


A  cleft palate  is one of the most common causes of VPI. Cleft palate is an anatomical abnormality that occurs in utero and is present at birth. This malformation can affect the lip and palate, or the palate only. A cleft palate can affect the mobility of the velopharyngeal valve, thereby resulting in VPI. [ citation needed ]


While cleft is the most common cause of VPI, other significant etiologies exist. These other causes are outlined in the chart below:


The most frequent types of cleft palates are overt, submucous, and occult submucous. [ citation needed ]


A common method to treat Velopharyngeal insufficiency is  pharyngeal flap surgery , where tissue from the back of the mouth is used to close part of the gap. Other ways of treating velopharyngeal insufficiency is by placing a posterior nasopharyngeal wall implant (commonly cartilage or collagen) or type of soft palate lengthening procedure (i.e. VY palatoplasty). [ citation needed ]


Velopharyngeal  insufficiency  or  incompetency  are related labels for this phenomenon, in addition to most common generic-  velopharyngeal   inadequacy .  Velopharyngeal insufficiency  is the inability of the velopharyngeal  sphincter  to sufficiently separate the nasal cavity from the oral cavity during  speech .  Velopharyngeal incompetency  occurs when the  soft palate  and the lateral/posterior pharyngeal walls fail to separate the oral cavity from the nasal cavity during speech. Although the definitions are similar, the  etiologies  correlated with each term differ slightly. However, in the field of medical professionals these terms are typically used interchangeably. [ citation needed ]


A  vestigial twin  is a form of  parasitic twinning , where the parasitic "twin" is so malformed and incomplete that it typically consists entirely of extra limbs or  organs . It also can be a complete living being trapped inside the host person, however the parasitic twin is  anencephalic  and lacks  consciousness . [ 1 ]


Most vestigial limbs are non-functional, and although they may have bones, muscles, and nerve endings, they are not under the control of the host. The limbs can pose problems in redirecting necessary resources such as blood to the nonfunctional limbs while the body lacks these resources. Additionally, the presence of six or more digits on the hands and feet ( polydactyly ) is typically caused by a  genetic  or  chromosomal  anomaly and is not considered a case of vestigial twinning.  [ 1 ]


Woman who are  pregnant  do not experience any different symptoms when carrying vestigial twins compared to a normal pregnancy.


Once the fetus is born, the presentation will typically consist of an extra  extremity  attached to the dominant twins body. Only the dominant fetus will be  viable . The limbs attached will contain  nerve endings ,  bones , and  tissue . In some cases, the fetus can be born with a attached limb as a "tail." This tail is the extension of the  coccygeal vertebra . [ 2 ]  The parasitic twins limbs can be attached to the dominant twin at more than one location, for example the  head ,  torso ,  pelvis ,  buttocks ,  back , etc.  [ 3 ]


This phenomenon occurs when a  fertilized   ovum  or partially formed embryo splits incompletely. The result is one dominant twin with extra body parts belonging to the vestigial twin. It is also possible for tail-like tissue to form around the  sacrum . [ 2 ]  One theory proposes that the usage of teratogenic drugs by the mother may be a factor in the development of vestigial parasitic twins. The cause for vestigial twins is still unclear. [ 4 ]


There is no way to prevent this from occurring. This disease is not contagious and occurs rarely in pregnancies. There are currently no  Centers for Disease Control and Prevention  recommendations on this, as this is a rare occurrence. [ 3 ]


This disease impacts pregnant women expecting twins. The reason why these twins do not fully separate is still unknown. Possible theories include abnormalities in  SHH ( sonic hedgehog) proteins . SHH proteins are vital for cell development, researchers believe this can cause the twins to be conjoined and then one stops developing. This then leads for the fetus to be born with a parasitic twin attached. Fission theory is another theory researchers believe causes vestigial . Fission theory would indicate the two fetuses in the womb began as  conjoined twins  and the parasitic twin stopped developing, leading to vestigial twins being born. The last theory researcher believe can potentially cause vestigial twins is fusion theory. According to the fusion theory there are two  fertilized eggs  in the womb that end up fusing together, this would create a fetus with the parasitic twins limbs attached. The dominant twin is impacted because the parasitic is somehow attached to their body. The parasitic twin can be attached at the head, torso, buttocks, back, etc. Vestigial twins occurs very rarely so it is unknown why the dominant twin is born with the parasitic twins limbs attached. [ 1 ]


Early diagnosis can be found during a  prenatal ultrasound . A prenatal ultrasound uses sound waves to show the fetus in the womb. [ 5 ]  However, there have been cases that it was not possible to diagnose the vestigial twin before birth using an ultrasound. There is no way to prevent vestigial twins or diagnose vestigial twins through pregnancy symptoms.Vestigial twins can be diagnosed before birth through an ultrasound or other imaging such as  MRI  or  Ct scan.  An MRI or CT scan can show how the twins are connected, After birth the diagnoses can be made by looking at the parasitic twin attached to the vestigial twin. An  obstetric and gynecology physician  can be treat and diagnose this patient, however a pregnant women would be referred to a maternal and  fetal medicine  specialist. It is possible to have different surgeons assigned to the case to assist with removing the parasitic twin. There have been cases where it is difficult to visualize the parasitic twins on an ultrasound, which would cause a delay in diagnoses until birth. If the expecting mother does not receive  prenatal  visits a delay in diagnosis would occur. However, once the vestigial twins are born it would be easily diagnosed during a physical exam. [ 6 ]


Treatment for vestigial twins typically includes having surgery to remove the parasitic twin. If the parasitic twin is not removed the risk for further complications increases significantly. The twin supporting the parasitic twin can have complications. Therefore, the best course of treatment would be to remove the attached parasitic twin. A healthcare provider would schedule additional tests to check to see if the fetus has any complications and treat them. Treatment for other complications would be different based on each case.  [ 1 ]


After the fetus undergoes the procedure to remove the parasitic twin there is a risk to developing  infection ,  hernia , and typical  surgical complications . There are no holistic treatment options other then leaving the parasitic twin attached, however leaving the parasitic twin attached to the dominant twin can lead to further complications for the dominant twin. The dominant twins body can be put under a lot of stress if still attached to the parasitic twin. Surgery to remove the parasitic twin is the only treatment to remove the parasitic twin from the dominant twin. [ 1 ]


The typical prognosis for the case studies that have been found is overall good once the parasitic twin is separated. If the host twin has some complications such as a  hernia  and or  infection  more treatment may be needed. The occurrence does not repeat after the parasitic twin is removed. [ 3 ]


It is unclear if there is an environmental or  hereditary  risk factor associated with vestigial twins. However, researchers believe that abnormalities in the  SHH protein  can create a risk or a possible explanation for having vestigial twins. [ 3 ]


Vestigial twins is a rare occurrence, it has been reported that it occurs less than 1 in 1 million births. Woman of child bearing ages that are pregnant with twins can be impacted.  Twin  fetuses that are still developing in the womb can become vestigial twins, although this is a rare occurrence. Since this occurrence is so sparse it is unclear whether it impacts different ethnicities or races. [ 7 ]  However, rachipagus parasiticus, an extremely rare type of parasitic twins, is most commonly reported in Ethiopia. Rachipagus parasiticus is where the parasitic twin is attached to the spine. [ 8 ]


There are currently no  clinical trials  available for vestigial parasitic twins. Since this is such a rare occurrence there is not enough patients or known to develop any drug treatments. It is unclear if any medications can be used to prevent or treat vestigial parasitic twins, however surgery to separate the twins has been proven to show positive outcomes. Researchers have two theories that they believe causes vestigial parasitic twins:  fission theory  and  fusion theory . [ 1 ]


Another potential cause researchers are investigating an abnormalities in SHH proteins. SHH, sonic hedgehog protein , plays an important role in development of  cells.  During embryonic development the SHH protein is responsible for the shaping of the body, cell specialization,  cell development . [ 9 ]  Researchers believe that potential  abnormalities  in this protein can put woman at higher risk for potentially having vestigial parasitic twin pregnancies.  [ 3 ]


Vici syndrome , also called  immunodeficiency with cleft lip/palate, cataract, hypopigmentation and absent corpus callosum  (or absent corpus callosum cataract immunodeficiency), [ 1 ]  is a rare  autosomal   recessive [ 2 ]   congenital disorder  characterized by  albinism ,  agenesis of the corpus callosum ,  cataracts ,  cardiomyopathy , severe  psychomotor retardation ,  seizures ,  immunodeficiency  and recurrent severe  infections . [ 3 ] [ 4 ]  To date, about 50 cases have been reported. [ 5 ]


This syndrome consists of a number of typical features. These include  [ citation needed ]


Infections of the gastrointestinal and urinary tracts are common. Swallowing and feeding difficulties early on may result in a failure to thrive. Optic nerve hypoplasia,  nystagmus  and  photophobia  may occur. Facial dysmorphism (cleft lip/palate and micrognathia) and syndactyly may be present. Sensorineural hearing loss may also be present. [ citation needed ]


Death in infancy is not uncommon and is usually due to cardiac complications or severe infections. [ citation needed ]


Vici syndrome is inherited in an autosomal recessive manner. [ 2 ]  This means the defective gene responsible for the disorder is located on an  autosome , and two copies of the defective gene (one inherited from each parent) are required in order to be born with the disorder. The parents of an individual with an autosomal recessive disorder both  carry  one copy of the defective gene, but usually do not experience any signs or symptoms of the disorder.
The hypothesis of autosomal recessive inheritance of Vici syndrome was strengthened in 2002 with the clinical description of two new cases, one brother and one sister, by Chiyonobu et al. [ 6 ]


Vici syndrome is caused by mutations in the gene  EPG5  (OMIM # 615068), which encodes an important regulator of the autophagy pathway, the ectopic P-granules autophagy protein 5, involved in the formation of lysosomes.
EPG5 is the human homolog of the C.elegans epg5 gene. The gene EPG5 has been cloned for the first time by Nagase et al. by sequencing clones obtained from a size-fractionated fetal brain cDNA library, and was initially named KIAA1632. [ 7 ]


The EPG5 human gene is located on chromosome 18q12.3, has a length of 119,67Kb (NC_000018.10), consists of 44 exons and is transcriptionally driven from the centromere toward the telomere. The messenger RNA (mRNA) is 12633bp long (NM_020964.2) and contains a CDS of 7740 bp translated into a protein sequence of 2579 amino acids (NP_066015.2) with a molecular weight of 280kDa, presumed. The protein EPG5 is expressed primarily in the central nervous system (CNS), skeletal muscle, heart, thymus, cells of the immune system, lungs and kidneys. [ 8 ]


Mutations in the EPG5 gene interfere with the autophagy. This appears to be due to a block in the autophagosome-lysosome fusion mechanism. [ 9 ]


The diagnostic workup usually includes an MRI of the brain, an EEG, ophthalmic examination and a cardiac ECHO. Muscle biopsy – which is not commonly done – may show storage of abnormal material and secondary mitochondrial abnormalities in skeletal muscle. Other features that may be seen on muscle biopsy include variability in fibre size, increase in internal and centralized nuclei, type 1 fibre hypotrophy with normally sized type 2 fibres, increased glycogen storage and variable vacuoles on light microscopy [ citation needed ]


The diagnosis is confirmed by sequencing of the EPG5. [ citation needed ]


This includes  ataxia–telangiectasia ,  Chédiak–Higashi syndrome ,  DiGeorge syndrome ,  Griscelli syndrome  and  Marinesco–Sjögren syndrome . [ citation needed ]


There is no known curative treatment presently. Hearing aids and cataract surgery may be of use. Control of seizures, heart failure, and treatment of infection is essential. Tube feeding may be needed. [ citation needed ]


Vici syndrome was first described by Carlo Dionisi-Vici et al. (Rome, Italy) in an article from 1988 about two brothers with a previously unreported disorder. [ 4 ]  Since then, a few articles have reported the same disorder, which subsequently obtained the name  Vici syndrome . [ 10 ] [ 2 ]


About 10 years later, del Campo et al. described 4 patients (including 2 sibs, a male and a female) with clinical features very similar to those reported by Dionisi-Vici. [ 11 ]


In 2007, the renal tubular acidosis was another clinical complication described in only one case report of two brothers with Vici syndrome. [ 12 ]


In 2010 and 2012, it has also been reported a neuromuscular involvement in patients suffering from this syndrome. [ 13 ] [ 14 ]


In 2013, Vici syndrome has been associated with mutations in the gene EPG5 (OMIM # 615068), which encodes an important regulator of the autophagy pathway, the ectopic P-granules autophagy protein 5, involved in the formation of lysosomes. [ 15 ]


In 2014, the ophthalmologic features of Vici syndrome were carefully evaluated. [ 16 ]


In 2015, the doctoral thesis entitled "Deciphering the mechanism of immune dysfunction in Vici Syndrome", University of Rome "La Sapienza" by Dr. Evangelos Axiotis, clarifies the molecular mechanisms and the role of the mutations in EPG5, all responsible for the immunodeficiency present in patients with Vici syndrome. [ citation needed ]


Walker–Warburg syndrome  (WWS), also called  Warburg syndrome ,  Chemke syndrome ,  HARD syndrome  (Hydrocephalus, Agyria and Retinal Dysplasia),  Pagon syndrome ,  cerebroocular dysgenesis  (COD) or  cerebroocular dysplasia-muscular dystrophy syndrome  (COD-MD), [ 1 ]  is a rare form of  autosomal   recessive   congenital   muscular dystrophy . [ 2 ]  It is associated with brain ( lissencephaly ,  hydrocephalus ,  cerebellar  malformations) and  eye  abnormalities. [ 3 ]  This condition has a worldwide distribution. Walker-Warburg syndrome is estimated to affect 1 in 60,500 newborns worldwide. [ 4 ]


The clinical manifestations present at birth are generalized  hypotonia , muscle weakness, developmental delay with  intellectual disability  and occasional  seizures . [ 5 ]  The congenital muscular dystrophy is characterized by hypoglycosylation of α-dystroglycan.
Those born with the disease also experience severe ocular and brain defects. Half of all children with WWS are born with encephalocele, which is a gap in the skull that will not seal. The meninges of the brain protrude through this gap due to the neural tube failing to close during development. A malformation of the a baby's cerebellum is often a sign of this disease. Common ocular issues associated with WWS are abnormally small eyes and retinal abnormalities cause by an underdeveloped light-sensitive area in the back of the eye. [ 6 ]


Several genes have been implicated in the etiology of Walker–Warburg syndrome, [ 7 ]  and others are as yet unknown. Several mutations were found in the protein  O-Mannosyltransferase   POMT1  and  POMT2  genes, and one mutation was found in each of the  fukutin  and  fukutin-related protein  genes. Another gene that has been linked to this condition is Beta-1,3-N-acetylgalactosaminyltransferase 2 ( B3GALNT2 ). [ 8 ]


Laboratory investigations usually show elevated  creatine kinase , myopathic/dystrophic muscle pathology and altered α-dystroglycan. Antenatal diagnosis is possible in families with known mutations. Prenatal ultrasound may be helpful for diagnosis in families where the molecular defect is unknown. [ 9 ]


No specific treatment is available. Management is only supportive and preventive.
Those who are diagnosed with the disease often die within the first few months of life. Almost all children with the disease die by the age of three. [ 9 ]


WWS is named for  Arthur Earl Walker  and  Mette Warburg  (1926-2015), a Danish ophthalmologist. [ 10 ] [ 11 ] [ 12 ]  Its alternative names include Chemke’s syndrome and Pagon’s syndrome, named after  Juan M. Chemke  and  Roberta A. Pagon . [ 10 ]


Weaver syndrome  is an extremely rare  autosomal dominant  genetic disorder associated with rapid growth beginning in the prenatal period and continuing through the toddler and youth years. It is characterized by advanced osseous maturation and distinctive craniofacial, skeletal and neurological abnormalities. [ 1 ]  It is similar to  Sotos syndrome  and is classified as an  overgrowth syndrome .


Its genetic cause was identified in 2011 as mutations in the  EZH2  gene. [ 2 ]  Forty-eight cases had been documented and confirmed as of December 2013 [update] , [ 3 ]  and its prevalence is estimated to be similar to that of Sotos syndrome, around 1 in 15,000. [ 4 ]  It was first described by American physician David Weaver in 1974. [ 5 ]


Children with Weaver syndrome tend to look similar and have distinctive physical and craniofacial characteristics, which may include several, but not all, of the following features:  [ 6 ]


Other features may include loose skin, thin deep-set nails, thin hair, short ribs, limited elbow and knee extension,  camptodactyly , and a coarse, low-pitched voice. Delayed development of motor skills such as sitting, standing, and walking are commonly exhibited in early childhood. Patients with Weaver syndrome typically have mild intellectual disability with poor coordination and balance. [ 7 ]  They also have some neurological abnormalities such as  speech delay ,  epilepsy ,  intellectual disability ,  hypotonia  or  hypertonia , and behavioral problems. [ citation needed ]


The cause for Weaver syndrome was identified in 2011 as  autosomal dominant  mutations in the  EZH2  gene on  chromosome 7q36 . [ 2 ]  EZH2 (Enhancer of Zeste, Drosophila, homolog 2) is the second  histone methyltransferase  associated with human overgrowth. It encodes the catalytic component of the  PRC2  protein complex (Polycomb Repressive Complex 2), which regulates chromatin structure and gene expression, and has been found to repress transcription. EZH2 also has critical roles in stem cell maintenance and cell lineage determination, such as  osteogenesis ,  myogenesis ,  lymphopoiesis  and  hematopoiesis .


It can also be associated with mutations in the histone methyltransferase  NSD1  gene on  chromosome 5q35 . The functions of NSD1 are not clearly known, but it is thought to act as a factor in influencing transcription, which contains domains involved in chromatin-mediated regulation during development. [ 8 ]


Most cases are found to be sporadic, with no family history of the syndrome, although there have been a few cases in families where autosomal dominant inheritance has been reported. [ 9 ]


Weaver syndrome and  Sotos syndrome  are often mistaken for one another due to their significant phenotypic overlap and similarities. [ 10 ]  Clinical features shared by both syndromes include overgrowth in early development, advanced bone age, developmental delay, and prominent  macrocephaly . [ 11 ]  Mutations in the NSD1 gene may also be another cause for confusion. The  NSD1  gene provides instructions for making a protein that is involved in normal growth and development. Deletions and mutations in the NSD1 gene is a common cause for patients with Sotos syndrome and in some cases for Weaver syndrome as well.  [ 6 ]


Features distinguishing Weaver syndrome from Sotos syndrome include broad forehead and face,  ocular hypertelorism , prominent wide  philtrum ,  micrognathia , deep-set nails,  retrognathia  with a prominent chin crease, increased prenatal growth, and a carpal bone age that is greatly advanced compared to metacarpal and phalangeal bone age. [ 12 ]


There is no cure available for Weaver syndrome. However, with multidisciplinary management, such as neurological, pediatric, orthopedic and psychomotor care and genetic counseling, symptoms can be managed. Surgery may be used to correct any skeletal issues. Physical and occupational therapy are considered an option to help with muscle tone. Also, speech therapy is often recommended for speech related problems. [ medical citation needed ]


With appropriate treatment and management, patients with Weaver syndrome appear to do well, both physically and intellectually, throughout their life and have a normal lifespan. [ medical citation needed ]  Their adult height can reach 7–8 feet (213.36–243.84 cm). [ 13 ]


The incidence of Weaver syndrome is uncertain, as the causative mutation was only identified in 2011. As of December 2013 [update] , 48 cases of Weaver syndrome had been documented and confirmed. [ 3 ] [ 14 ]  In 2012, the South West Thames Regional Genetic Service at  St George's Hospital  in London, based on their detection rate among a cohort of patients within their Childhood Overgrowth Study, estimated a prevalence rate similar to that of Sotos syndrome, around 1 in 15,000. [ 4 ]


Weissenbacher–Zweymuller syndrome  (WZS), also called  Pierre-Robin syndrome with fetal chondrodysplasia , [ 1 ]  is an  autosomal   recessive [ 2 ]   congenital disorder , linked to  mutations  (955  gly  ->  glu ) in the  COL11A2   gene  (located on  chromosomal  position 6p21.3), which codes for the α 2  strand of  collagen  type XI. [ 1 ] [ 2 ]  It is a  collagenopathy, types II and XI  disorder. The condition was first characterized in 1964 by G. Weissenbacher and Ernst Zweymüller. [ 3 ] [ 4 ]


The disorder causes facial abnormalities, skeletal malformation and occasionally  neural tube defects ; the skeletal disfigurements resolve to a degree in the course of development. [ citation needed ]


Mutations in different parts of the gene may lead to  deafness  or  Stickler syndrome  type III ( myopia ,  retinal detachment  and skeletal abnormalities). [ citation needed ]


Infants and children: Infants that are born with Weissenbacher-Zweymüller syndrome usually have short bones in their arms and legs. [ 5 ]  The thigh and upper arm bones are wider than usual resulting in a dumbbell-shape while the bones of the vertebrae may be abnormal. [ 5 ]  Typical abnormal facial features can be wide-set protruding eyes (hypertelorism), a small and upturned nose with a flat bridge, small jaw (micrognathia) and a cleft palate. Some infants have high-frequency hearing loss. [ 5 ]   Infants may also exhibit a psychomotor delay. [ 6 ]  After the period of growth deficiency the individual makes improvements in bone growth leading to a normal physical development around age 5 or 6. [ 6 ]


Adults: Many with Weissenbacher-Zweymüller syndrome have a catch-up growth phase causing the adults to not be unusually short. Many adults still will have hearing loss and typical abnormal facial features of Weissenbacher-Zweymüller syndrome. [ 5 ]


Dominant genetic disorders can be caused by just a single copy of an abnormal gene. This abnormal gene can be the result of being inherited from either parent or be a new mutation. [ 6 ]  Most cases are caused by a de novo (new) mutation in the gene that occurs during the formation of the egg or sperm. These cases occur when there is no history of the disorder in the family.
The COL11A2 gene is responsible for providing instructions on making one component of the type XI collagen. [ 5 ]  Type XI collagen is a complex molecule that helps give structure and strength to the connective tissues. [ 5 ]  Collagen is found in bone. It is also found in cartilage that makes up most of the skeleton during early development. The mutation of COL11A2 in Weissenbacher-Zweymüller syndrome disrupts the assembly of the type XI collagen molecules. [ 5 ]  The malfunctioning collagen weakens the connective tissue causing impaired bone development. [ 5 ]
COL11A2 is also associated with autosomal dominant non-syndromic hearing loss (ADNSHL). [ 7 ]  All mutations of COL11A2 in ADNSHL are missense mutations. [ 7 ]


Weissenbacher-Zweymüller syndrome is diagnosed upon a thorough clinical evaluation, detailed patient history, identification of characteristic symptom and a variety of specialized tests which includes x-rays.
 [ 6 ]


Because there is no cure, treatment is directed towards the specific symptoms that are present in each individual. [ 6 ]


Weissenbacher-Zweymüller syndrome affects males and females in the same numbers. About 30 cases have been reported in medical literature. [ 6 ]  The disorder can be underdiagnosed causing no true frequency in the population. [ 6 ]


Wilson-Turner syndrome  ( WTS ), also known as  mental retardation X linked syndromic 6  ( MRXS6 ), and  mental retardation X linked with gynecomastia and obesity  is a congenital condition characterized by intellectual disability and associated with childhood-onset obesity. [ 1 ]  It is found to be linked to the  X chromosome  and caused by a mutation in the  HDAC8  gene, which is located on the q arm at  locus  13.1. Individuals with Wilson–Turner syndrome have a spectrum of physical characteristics including  dysmorphic  facial features,  hypogonadism , and short stature. Females generally have milder phenotypes than males.  This disorder affects all demographics equally and is seen in less than one in one million people. [ 2 ]


The study of X-linked mental retardation began in 1943 when Martin and Bell reported a family exhibiting  sex-linked  mental retardation. [ 3 ]  However, this syndrome was not recognized until 1991. Wilson studied 14 males from three successive generations that presented hypogonadism, mental retardation,  gynecomastia , and short stature, among other symptoms. [ 4 ]  Eventually, this disorder was ruled distinct from a syndrome presented by Prader and Willi ( Prader-Willi syndrome ) because of its mode of inheritance, gynecomastia, and the presence of small hands and feet. [ 5 ]  However, there is some speculation that this syndrome is in the same spectrum as the  Cornelia de Lange syndrome . [ 6 ]


The most notable features of Wilson–Turner syndrome are intellectual disability, obesity, hypogonadism, gynecomastia, and distinct facial features. All of the symptoms are chronic. Affected females are known to have less severe signs and symptoms than males. Female carriers of the disorder may have mild or no symptoms.


The only known cause of this disorder is the mutation on the HDAC8 gene, which is located at Xq13.1. This disorder displays X-linked inheritance.


The primary symptoms of Wilson-Turner Syndrome is believed to result from an improperly developed  histone deacetylase  8. This enzyme is coded by the HDAC8 gene. The identified mutation in the HDAC8 gene leads to a version of histone deacetylase 8 that is missing a segment. Histone deacetylase 8 is believed to be a regulator of the cohesion complex, playing a role in stabilizing the cell's genetic information, repairing damaged DNA, and controlling gene activity.  This abnormally shortened protein alters gene regulations during the individual's normal development. Some of the effected normal development lies in the  endocrine system . Males will have more  estrogen  and  androgen  than normal, leading to enlarged hypogonadism and gynecomastia. Other abnormal development is related to general mental capacity. [ 6 ]   HDACs  are known to be associated with human brain development disorders. [ 1 ]  HDAC8, in particular, represses transcription factors in neural crest cells to control various patterns of the skull. [ 1 ]  This contributes to the various forms of facial deformities in individuals with Wilson-Turner Syndrome. Some of the facial deformities caused by the HDAC8 include prominent supraorbital ridges and high cheekbones. Researchers also contribute the error in the HDAC8 gene to obesity. Since the HDAC family proteins are involved in changes in the gene expression in the  hypothalamus , it is also believed that the individual's  metabolism  conditions are altered. [ 15 ]


The diagnosis of Wilson–Turner syndrome is based upon a clinical evaluation, a detailed patient history, and identification of characteristic features. Molecular  genetic testing  for mutations in the HDAC8 gene is now available to confirm the diagnosis.


The Wilson–Turner syndrome is characterized by mild to moderate range of intellectual disability, obesity, tapered fingers, and mood swings. Males also have gynecomastia and hypogonadism. In order to be diagnosed with Wilson-Turner Syndrome, male patients must have intellectual disability, obesity, and gynecomastia. Females do not necessarily have to have noticeable phenotype but can be diagnosed with this disorder by studying her family history and identifying others with the disorder. It has been noted that children with Wilson-Turner Syndrome will display speech development delay and excessive drooling. Males can be confirmed by testing androgen levels. [ 8 ]  Female carriers will show silencing of the gene a complex  X inactivation . [ 16 ]


Family medical history is studied in depth due to its X-linked inheritance. The families that were studied and diagnosed with Wilson-Turner Syndrome have shown X-linked recessive pedigree pattern. This disorder only have been identified in two families, thus there is still ongoing studies concerning other inherited factors that may contribute to this disorder. [ 16 ]


Screening methods are mostly done for females to determine if they are carriers. Males do not have to be tested because those with the disorder will show symptoms close to the time they are born because the disorder is inherited from the X chromosome. Females can be tested if they are carriers by performing a X chromosome inactivation analysis on DNA isolated from the peripheral lymphocytes. The CAG repeat in this section must be amplified and methylated DNA must be sorted from unmethylated DNA with PCR. Carrier females will show skewed X-inactivation pattern (skewing close to 100%) with the mutated  allele  inactivated. This indicates a selection against cells with an active X chromosome with the mutated HDAC8 gene. [ 1 ]


There is no known cure available for Wilson–Turner syndrome. Instead, treatment options are available to fight individual symptoms. For obesity, a nutritional diet manipulation is combined with an exercise regimen that has a greater energy expenditure than intake. For hypogonadism,  testosterone replacement  is done. For gynecomastia, weight loss using similar methods for obesity is prescribed. However, if the individual finds their increased breast tissue psychologically distressing or too severe, reduction  mammaplasty  is done. Currently, researchers are investigating therapies using antiestrogens and  aromatase inhibitors  to treat persistent pubertal gynecomastia. [ 17 ]


Unlike  Borjeson-Forssman-Lehmann syndrome , a disorder that was determined to be very similar to WTS, the individuals with Wilson–Turner syndrome do not develop  cataracts  or  hypermetropia  later in life. [ 18 ]  By far, the most debilitating part of this disorder is intellectual disability. Many of the other symptoms are more easily managed through  hormone treatment , proper diet and exercise, and  speech therapy .


This disorder affects all demographics equally. The two families that were studied are of European ancestry. Wilson–Turner syndrome is considered to be a rare disease because it affects one individual out of one million. [ 2 ]


In 2012, a study of a five-generation Dutch family consisting of seven males and seven females with Wilson–Turner syndrome. These individuals had some characteristics that differed from the stated phenotype mentioned by Wilson. These individuals have a larger stature, head, and chin, in addition to coarse facial features. Unlike the females in Wilson's study, these females showed signs of being affected, although less severe than their male counterparts. None of the men could live on their own. Studies verified that the phenotype of the disorder range on a large scale and can affect everyone differently. This research group also used  next-generation sequencing  of the X chromosome  exome  to identify the HDAC8 gene mutation [ 1 ]


There is also ongoing research to determine the cause of the decreased or low androgen levels. It is studying the possible disturbance of the  hypothalamic-pituitary-gonadal axis  because of the low levels of androgen are combined with normal levels of  FSH  and  LH . [ 7 ]


Worth syndrome , also known as  benign form of Worth hyperostosis corticalis generalisata with torus platinus ,  autosomal dominant osteosclerosis ,  autosomal dominant endosteal hyperostosis  or  Worth disease , [ 1 ] [ 2 ]  is a rare  autosomal   dominant   congenital disorder  that is caused by a mutation in the  LRP5  gene. [ 3 ]  It is characterized by increased  bone  density and  benign  bony structures on the  palate . [ 1 ] [ 3 ] [ 4 ] [ 5 ]


Worth syndrome is caused by a  mutation  in the  LRP5  gene, located on human  chromosome   11q13.4 . [ 3 ] [ 6 ]  The disorder is inherited in an autosomal dominant fashion. [ 1 ]  This indicates that the defective gene responsible for a disorder is located on an  autosome  (chromosome 11 is an autosome), and only one copy of the defective gene is sufficient to cause the disorder, when inherited from a parent who has the disorder. [ citation needed ]


The condition was first reported by  H. M. Worth  in 1966. In 1977, two  doctors , R.J. Gorlin and L. Glass, distinguished the syndrome from  van Buchem disease . In 1987 a group of  Spanish  doctors pointed out that the condition may not be  benign , and may sometimes cause  nerve  damage. [ 1 ]


XX male syndrome , also known as  de la Chapelle syndrome , is a rare intersex condition in which an individual with a 46,XX  karyotype  develops a male  phenotype . [ 2 ]  Synonyms for XX male syndrome include  46,XX testicular difference of sex development  (or 46,XX DSD) [ 3 ] [ 4 ] [ 5 ] [ 6 ]


In 90 percent of these individuals, the syndrome is caused by the  Y chromosome 's  SRY  gene, which triggers male reproductive development, being atypically included in the  crossing over  of genetic information that takes place between the  pseudoautosomal regions  of the X and Y chromosomes during  meiosis  in the father. [ 2 ] [ 7 ]  When the X with the  SRY  gene combines with a normal X from the mother during  fertilization , the result is an XX male. Less common are  SRY -negative XX males, which can be caused by a mutation in an  autosomal  or X chromosomal gene. [ 2 ]  The masculinization of XX males is variable.


This syndrome is diagnosed  and occurs in approximately 1:20,000 new-born males, making it much less common than  Klinefelter syndrome . [ 8 ] [ 9 ] [ 10 ]  Medical treatment of the condition varies, with medical treatment usually not necessary. The alternative name for XX male syndrome, de la Chapelle syndrome, refers to Finnish scientist  Albert de la Chapelle , who first described the condition. [ 11 ]


While there is some degree of variability, a vast majority of XX males have a typical male phenotype, with male-typical external genitalia, making early diagnosis uncommon. [ 12 ] [ 13 ]  Genital ambiguity is seen most commonly in men without the SRY gene/other Y chromosome-derived genes, though reported rates are inconsistent. [ 13 ] [ 14 ] [ 9 ]  These ambiguities can include traits such as  hypospadias ,  micropenis , and  cryptorchidism . [ 15 ]  In most SRY-positive men, there are few significant signs before puberty, though small testes appear an almost universal finding; following puberty, some XX males develop gynaecomastia. [ 13 ] [ 1 ] [ 16 ]  XX males appear to be shorter on average than XY males. [ 2 ] [ 1 ]


Based on limited evidence, most XX males appear to have typical body and pubic hair, penis size, libido, and erectile function. [ 13 ]  In all reported cases, individuals have been sterile, with azoospermia (no sperm in the ejaculate). [ 17 ] [ 16 ]  One study found spermatogonia – undifferentiated cells which develop into sperm – present in some XX male children, the oldest of which was 5 years old, but none in the older XX males tested. [ 18 ]  Multiple studies in mice have also found largely normal male-type germ cells in XX males soon after birth, but a progressive loss with maturation. [ 19 ] [ 20 ]


Due to its often-subtle presentation, many XX males remain undiagnosed until seeking treatment for infertility in adulthood; it's likely a significant proportion of cases remain undiagnosed. [ 12 ] [ 9 ]


The degree to which individuals with XX male syndrome develop the male phenotype is variable, even among SRY-positive individuals. [ 21 ]


Masculinization of SRY-positive XX males is believed to be dependent on which X chromosome is made inactivate. Typical XX females undergo  X inactivation  during which one copy of the X chromosome is silenced. It is thought that X inactivation in XX males may account for the genital ambiguities and incomplete masculinization seen in SRY-positive XX males. [ 22 ] [ 21 ]  The X chromosome with the SRY gene is preferentially chosen to be the active X chromosome 90% of the time, which explains complete male phenotype being observed often in SRY-positive XX males. [ 22 ] [ 21 ]  In the remaining 10%, however, X inactivation occurs on the X chromosome with the SRY gene, thereby silencing it and resulting in incomplete masculinization. [ 22 ] [ 21 ]


Masculinization of SRY-negative XX males is dependent upon which genes have mutations and at what point in development these mutations occur. [ 23 ]


Males typically have one X chromosome and one Y chromosome in each  diploid  cell of their bodies. Females typically have two X chromosomes. XX males that are SRY-positive have two X chromosomes, with one of them containing genetic material (the  SRY gene ) from the Y chromosome; this gene causes them to develop a male phenotype despite having chromosomes more typical of females. [ 2 ]  Some XX males, however, do not have the SRY gene (SRY-negative); the reason a male phenotype develops in these individuals is poorly understood, and subject to further research. [ 24 ]


The SRY gene, normally found on the Y chromosome, plays an important role in sex determination by initiating testicular development. In about 80 percent of XX males, the SRY gene is present on one of the X chromosomes.  [ 16 ] [ 25 ]


The condition results from an abnormal exchange of genetic material between chromosomes (translocation). This exchange occurs as a random event during the formation of sperm cells in the affected person's father. The tip of the Y chromosome contains the SRY gene and, during  recombination , a  translocation  occurs in which the SRY gene becomes part of the X chromosome. [ 15 ] [ 26 ]  If a fetus is conceived from a sperm cell with an X chromosome bearing the SRY gene, it will develop as a male despite not having a Y chromosome. This form of the condition is called SRY-positive 46,XX testicular disorder of sex development. [ 3 ]


About 20 percent of those with 46 XX testicular disorder of sex development do not have the  SRY gene . This form of the condition is called SRY-negative 46,XX testicular disorder of sex development. The cause of the disorder in these individuals is often unknown, although changes affecting other genes have been identified. Individuals with SRY-negative 46,XX testicular disorder of sex development are more likely to have ambiguous genitalia than are people with the SRY-positive form. [ 3 ] [ 2 ]


The exact cause of this condition is unknown, but three theories have been proposed: first, undetected gonadal mosaicism for SRY; second, de-repression of male development due to mutations in genes on chromosomes other than the Y chromosome; third, altered expression of other genes downstream of SRY, resulting in masculinisation. [ 27 ]  For example, it has been proposed that mutations in the  SOX9  gene may contribute to this syndrome, as SOX9 plays a role in testes differentiation during development. [ 28 ] [ 23 ]  Another proposed cause is mutations to the  DAX1  gene, which may suppress masculinisation; if there is a  loss of function  of DAX1, then testes can develop in an XX individual. [ 29 ]   [ 30 ]  Mutations in  SF1  and  WNT4  genes have also been studied in connection with SRY-negative 46 XX female  xx male syndrome . [ 29 ]


There is no consensus on the diagnostic criteria; diagnosis typically involves evaluating the individual's physical development in combination with karyotyping, and presence of the SRY gene or associated genes, such as SOX9. Tests for hormone levels and azoospermia may also be completed. [ 31 ]


Most XX males have a typical male-type phenotype at birth, so diagnosis tends to occur either at the onset of puberty, if traits such as gynaecomastia develop and are investigated, or later, when investigating infertility. [ 9 ] [ 24 ]  Diagnosis at birth occurs more frequently in SRY-negative XX males, who are more likely to have ambiguous genitalia. [ 14 ] [ 9 ]


In cases where the individual is being evaluated for ambiguous genitalia, such as a small phallus,  hypospadias , or labioscrotal folds, exploratory surgery may be used to determine if male and/or female internal genitalia is present. [ 32 ]  Indicators include two testes which have not descended the  inguinal canal , although this is seen in a minority of XX males, and the absence of  Müllerian tissue . [ 33 ]  External indicators include decreased body weight, gynecomastia, and small testes. [ 2 ]


A standard  karyotype  can be completed to  cytogenetically  determine that an individual with a partial or complete male phenotype has an XX genotype. [ 15 ] [ 32 ] [ 5 ]


The presence and location of the SRY gene can by determined using fluorescence  in situ  hybridization ( FISH ). [ 2 ] [ 21 ]


Treatments are generally focused on affirming the gender presentation of affected men, vary to a large degree based on the phenotype of the individual, and may include counselling. [ 34 ]  In some XX males, testosterone therapy may be used to increase virilisation. [ 25 ]  While the vast majority of XX males have typical male external genital development, cases of genital ambiguity may be treated with hormonal therapy, surgery, or both. In some cases, gonadal surgery can be performed to remove partial or whole female genitalia. This may be followed by plastic and reconstructive surgery to make the individual appear more externally male. [ 35 ]  Conversely, the individual may wish to become more feminine and feminizing genitoplasty can be performed to make the ambiguous genitalia appear more female. [ 36 ]


There is no treatment for infertility in XX males – supportive management and alternatives such as sperm donation or adoption are recommended. [ 37 ]


It is estimated that 1 of every 20,000 to 30,000 males has a 46,XX karyotype, making it much less common than other related syndromes, such as  Klinefelter syndrome . [ 2 ] [ 8 ] [ 9 ] [ 10 ]


Young–Simpson syndrome  ( YSS ) is a rare  congenital disorder  with symptoms including  hypothyroidism ,  heart defects ,  facial   dysmorphism ,  cryptorchidism  in males,  hypotonia ,  intellectual disability , and  postnatal   growth retardation . [ 1 ] [ 2 ]


Other symptoms include transient hypothyroidism,  macular degeneration , and  torticollis . [ 3 ]  The condition was discovered in 1987 and the name arose from the individuals who first reported the syndrome. [ 4 ] [ 5 ]  An individual with
YSS has been identified with having symptoms to a similar syndrome known as  Ohdo Blepharophimosis syndrome , showing that it is quite difficult to diagnose the correct condition based on the symptoms present. [ 6 ]  Some doctors therefore consider these syndromes to be the same. [ 7 ]


Ohdo syndrome, SBBYSS variant, typically occurs early in life, with most diagnoses occurring at birth or during infancy. Patients with SBBYSS variant of Ohdo syndrome are characterized with hyperthyroidism, heart defects, facial dysmorphism, hypotonia, mental retardation, and postnatal growth retardation.


Source [ 8 ]


Underdeveloped patellae (kneecaps) are the most common skeletal symptom associated with the syndrome. Additionally, abnormally long thumbs and great toes as well as dental abnormalities are also common among patients. Joint stiffness involving the hips, knees, and ankles is common which impairs movement among patients. Polydactyly, camptodactyly, clinodactyly, brachydactyly, syndactyly, club feet, and abnormalities of the spine and/or ribs may affect patients with the syndrome.


Source [ 9 ]


Facial signs and symptoms are most distinguishable among patients of this syndrome. Patients with Ohdo syndrome, SBBYS syndrome are characterized to have non-expressive mask-life faces. Additionally, patients may have features such as broad nasal bridges, nose with rounded top, narrowing of the eye opening, and prominent cheeks. Patients with the syndrome may also have abnormalities of the lacrimal glands and may be born with an opening in the roof of the mouth (cleft palate).


Source [ 10 ]