Segmental hypoplasia  or Ask-Upmark kidney is a rare  renal disease  where a part of the  kidney  has undergone  hypoplasia . The number of  renal lobes  is reduced, and the kidney size is less than two  standard deviations  from the average, with the weight often being over 50g in adults and 12–25g in children. This type of hypoplasia can be either unilateral or bilateral and is more prevalent in  females  by 72%. The  enzyme   renin  is overly  secreted , causing  hypertension  and is often severe.  Calyces  are enlarged,  glomeruli  are absent in the  cortex , and the  medulla  is either non-existent or underdeveloped.  Vesicoureteral reflux  and  urinary tract infections  are commonly present, while  cysts ,  dysplasia , and  proteinuria  are absent. The surface of the kidney has a pelvic recess and one or more transverse cortical grooves, presumed to be a failed formation of a renal lobe. The  renal parenchyma  next to the hypoplastic part of the kidney is seemingly normal; however, it can undergo  hypertrophy , making the grooves more noticeable. [ citation needed ]


Cortical hypoplasia is a not widely known type of renal  hypoplasia  where the number of  nephron  generations is reduced, causing the  renal medulla  to reduce in size and the  renal cortex  to decrease in thickness throughout the person's life. This type of hypoplasia is frequently paired with other forms of renal hypoplasia and seems to portray an arrest of  nephrogenesis , leading to fewer nephron generations, resulting in smaller renal size in general. The nephrogenesis before the arrest is normal. On the other hand, the  medullary rays  and  renal pyramids  have decreased in size with the radial glomerular count reduced to eight or less. [ 8 ]


Hypoplastic kidneys have a reduced  nephron  number, [ 4 ]  but normal corticomedullary differentiation. [ 1 ] [ 9 ]  The condition is usually asymptomatic, [ 10 ]  otherwise infection and  kidney stone  formation can occur. [ 5 ]


Renal hypoplasia is a common cause of  kidney failure  in children and also of adult-onset disease. [ 4 ]


We find the etiology of this condition is in the mutations in kidney-related genes, namely, HNF1B, PAX2, PBX1. However,   environmental factors like maternal diseases such as  diabetes ,  hypertension , and intoxication via smoking and  alcohol  are linked to renal hypoplasia. [ 10 ]


In terms of the diagnosis of renal hypoplasia, we find that the following is done in its evaluation: [ 1 ] [ 10 ] [ 11 ]


In terms of the treatment of renal hypoplasia, we find it depends on the severity of the chronic kidney disease.  Renal replacement therapy  is a possibility. [ 10 ]


Epidemiologic studies point to an estimated incidence of 1 in 400 births. [ 4 ]


The word  renal  comes from the  Late Latin  word  renalis  ("related to the kidneys"), from the  Latin  word  renes  ("kidneys"). [ 12 ]


The prefix  hypo-  comes from the  Ancient Greek  word ὑπο  hupo  ("under"). [ 13 ]


The suffix  -plasia  comes from the  Neo-Latin  word  plasia , from the  Ancient Greek  word πλάσις  plásis  ("molding, formation"). [ 14 ]


Renal–hepatic–pancreatic dysplasia  is an  autosomal   recessive   congenital disorder  characterized by  pancreatic   fibrosis ,  renal dysplasia  and  hepatic  dysgenesis. An association with  NPHP3  has been described. [ 1 ]
It was characterized in 1959. [ 2 ] [ 3 ]


Renal–hepatic–pancreatic dysplasia (RHPD) is characterized by unusual kidney cell development, [ 4 ]  disrupted liver development, [ 5 ]  and hardening or thickening scar tissue [ 6 ]  in the pancreas.


Through observation of fetuses that had passed away, it was determined that this syndrome has key representative external and microscopic appearances that can help diagnose the condition. The kidneys in many cases, appear to be enlarged, with cysts distributed throughout the tissue. Molecularly, many basic nephron structures, the part of the kidney that produces urine, [ 7 ]  are not identifiable or present. The appearance of the liver is often firm, with many cysts throughout. Microscopically, irregular bile duct development is detected, further restricted by thick scar tissue. The pancreas typically consisted of disorganized tissue and ducts that were dilated and not thoroughly developed. It was occasionally covered in cysts, with thick scar tissue throughout the organ. [ 8 ]


Although these observable features remain moderately consistent throughout various cases, other symptoms are case-specific, which has concluded that this syndrome does not have a homogenous display. Additionally, the disruption to liver development may be progressive since it does not arise in line with the kidney and pancreatic disturbances. [ 8 ]


Changes in genes associated with Nephronophthisis (NPHP — a common genetic disorder that causes kidney diseases in younger populations) [ 9 ]  have been identified as the probable genetic cause for renal failure in the first 3 decades of life and can develop as renal cysts. 10 genes were found to be responsible for NPHP: NPHP1-6, Glis2/NPHP7, RPGRIPL1/NPHP8, NEK8/NPHP9, and MKS3/NPHP11. [ 10 ] [ 11 ]  Mutations in  NPHP3  are heavily involved with RHPD. [ 10 ]


A chromosome with 1 rare variant copy (heterozygous NPHP3/nphp3) leads to reduced expression and is a known cause of cystic kidney disease. This differs from a chromosome where both copies are rare variants. [ 10 ]  2 variant copies of NPHP3 in humans will result in situs inversus (organs develop in flipped mirror image), [ 12 ]  polydactyly (born with extra fingers), [ 13 ]  central nervous system malformations, structural heart defects, preauricular fistulas (external ear disease), [ 14 ]  and a wide range of physical variation of the kidney and urinary tract structures. [ 11 ]


The role of protein kinases is to move a phosphate group from a high-energy molecule (adenosine triphosphate - ATP) to other molecules. These play a crucial role in the regulation of many biological processes [ 15 ]  NIMA Related Kinases (NEK) are involved in the regulation of cilia (small hair-like structures on the surface of cells) and pathways that initiate on the cell surface – especially the  Hippo pathway  which is involved in organ development. [ 16 ]   Mutations or alterations of NEK8 sequence can result in major organ development issues through alterations of the Hippo pathway. [ 16 ]


Different alterations to the NEK8 gene sequence can have varying impacts on organ development and formation of cilia. If the alteration causes NEK8 to be non-functional, it can result in kidneys and pancreas becoming enlarged and developing cysts. Alterations in  NEK8  that slightly change its genetic sequence can cause asymmetric growth of kidney cells (dysplasia) and the dilation of tubes necessary for returning vital substances back to blood after the filtering process and removing waste in kidneys. [ 16 ]


The research identifies 17 cases of reported RHPD, of which 4 of 17 surpassed age one, and 2 received organ transplantation. The 4 patients that survived past age one required  kidney dialysis  treatments, suffered from malnutrition and had a range of heart problems, including heart enlargement and heart vessel narrowing. Those who did not receive organ transplantation progressed into late-stage kidney failure combined with heart and liver complications that eventually led to death, leaving their quality of life to be very poor. [ 17 ]


Currently, there are no treatments for RHPD that relieve all its symptoms collectively. However, there are treatments for many of the symptoms separately that can reduce the disease load on the patient. To treat kidney disease, renal dialysis can be utilized. [ 18 ]  The treatment for heart vessel narrowing is an aortic valve replacement. [ 19 ]  Currently, there is no approved treatment for the thickening of pancreatic scar tissue, however, you can reduce ongoing damage by avoiding the consumption of alcohol and reducing fat food intake. [ 20 ]


Riboflavin-responsive exercise intolerance  ( SLC25A32 deficiency ) is a rare disorder caused by mutations of the SLC25A32 gene that encodes the  mitochondrial folate transporter . Patients suffer from exercise intolerance and may have disrupted motor function.


A positive correlation between SLC25A32 dysfunction and flavoenzyme deficiency has been observed suggesting that SLC25A32 is in fact a mitochondrial  FAD  transporter. In mice studies, besides β-oxidation and amino acid metabolism being impaired by mitochondrial FAD deficiency, Slc25a32 wipeout embryos experienced dysfunction of the glycine cleavage system–  dihydrolipoamide dehydrogenase . This  dihydrolipoamide dehydrogenase  dysfunction disrupted folate-mediated one-carbon metabolism, leading a deficiency of 5-methyltetrahydrofolate. [ 1 ]


Patients suffer from  exercise intolerance  and may also have neuromuscular symptoms such as  ataxia ,  dysarthia  and muscle weakness. Staining of skeletal muscle samples with hematoxylin and eosin may reveal the  ragged red fibers  sign indicating disrupted mitochondrial function. In some patients,  hypoketotic hypoglycemia  was described. [ 2 ]


Treatment with  riboflavin ,  5-formyltetrahydrofolate (Folinic acid)  and/or  L-5-methyltetrahydrofolate (5-MTHF)  may lead to a drastic improvement of symptoms.  Pyridoxal - 5 - Phosphate (P5P) , a cofactor for the enzyme  Serine hydroxymethyltransferase , may also assist with the conversion of  tetrahydrofolate  (THF) to  5,10-Methylenetetrahydrofolate  (5,10-CH 2 -THF) a direct precursor to  L-5-methyltetrahydrofolate (5-MTHF) .


Riboflavin - responsive exercise intolerance was first described in 2016 by Schiff et al. [ 3 ]


RIDDLE syndrome  is a rare genetic syndrome. The name is an acronym for Radiosensitivity, ImmunoDeficiency Dysmorphic features and Learning difficulties.


The features of this condition include: [ citation needed ]


This condition is due to mutations in the  RNF168  gene. It is inherited in an autosomal recessive fashion. The gene encodes a  ubiquitin   ligase  and is located on the long arm of  chromosome 3  (3q29) on the Crick (minus strand). [ 1 ]


The DDx is  [ citation needed ]


This condition is extremely rare. Only four cases have been described up to 2017. [ 2 ]


This syndrome was first described by Stewart et al. 2007. [ 3 ]


Ring chromosome 14 syndrome  is a very rare human  chromosome abnormality . It occurs when one or both of the  telomeres  that mark the ends of  chromosome 14  are lost, allowing the now uncapped ends to fuse together – thus forming a  ring chromosome . It causes a number of serious health issues. [ 1 ] [ 3 ] [ 4 ]


The most common symptoms are intellectual disability and recurrent  seizures  developing in infancy or early childhood. Typically, the seizures are resistant to treatment with  anti-epileptic  drugs. Other symptoms may include: [ 1 ] [ 5 ]


The syndrome is caused by the  loss of genetic material  near the end of the long arm (q) of  chromosome 14  . The break that causes the telomere(s) to be lost occurs near the end of the chromosome, and is called a  constitutional ring . These rings arise spontaneously ( it is rarely inherited). [ 4 ] [ 1 ] [ 6 ] [ 2 ]


The genetic abnormality occurs randomly in sperm or egg cells or it may occur in early embryonic growth, if it occurs during embryonic growth the ring chromosome may be present in only some of a person's cells. [ medical citation needed ]


Diagnosis is achieved by examining the structure of the chromosomes through  karyotyping ; [ 7 ]  while once born, one can do the following to ascertain a diagnosis of the condition: [ 2 ]


In terms of the management of ring chromosome 14 syndrome,  anticonvulsive  medication for seizures, as well as, proper therapy to help prevent  respiratory infections  in the affected individual are management  measures  that can be taken. [ 2 ]


Ring chromosome 14 syndrome is extremely rare, the true rate of occurrence is unknown (as it is  less than  1 per 1,000,000), but there are at least 50 documented cases in the literature. [ 9 ]


Ring chromosome 15  (sometimes denoted as  r15 ) is a condition that arises when  chromosome 15  fuses to form a  ring chromosome . Usually, ring chromosome 15 forms due to the modification or deletion of  genetic information  on chromosome 15 in the preliminary stages of embryonic development, but it can rarely also be inherited. [ 1 ]


All chromosomes have the capacity to form ring chromosomes. The symptoms and severity largely depend on the amount and location of the genetic information lost. [ 2 ]  If the ends of the chromosome fuse with no loss of genetic material, the individual retains the normal  phenotype  with relatively slight differences. However, evidence suggests that when there is deletion of genetic information at the distal unstable ends where the subtelomeric structures fuse, syndromes associated with that particular chromosome arise. [ 3 ]


Treatment for ring chromosome 15 predominantly targets the management of these symptoms rather than the chromosome ring itself.


Reported cases are few in number, and the phenotype expression for ring chromosome 15 syndrome occurs over a wide spectrum. [ 4 ] [ 5 ] [ 6 ]  As well, the cells of patients can have different levels of  mosaicism , creating even greater variation in the presence and severity of expression. [ 2 ]  Thus, while a precise  genotype–phenotype association  hasn't been fully established, [ 2 ]  common features associated with the syndrome have been determined.


An examination of 25 cases showed that  growth deficiency  (present in 100% of reviewed cases), some degree of  intellectual disability  (95%), and  microcephaly  (88%) are the most common developments. [ 4 ]  Other less frequent symptoms include delayed bone age (75%),  hypertelorism  (46%),  brachydactyly  (44%),  triangular face  (42%),  speech delay  (39%),  frontal bossing  (36%), anomalous ear (30%),  café au lait spots  (30%),  cryptorchidism  (30%) and cardiac abnormalities (30%). [ 4 ]


Research into ring chromosome 15 generally attempts to elucidate the causes of symptoms. For example, growth retardation may be caused by terminal deletion of the region 15q26, [ 7 ]  leading to  insulin–like growth factor I  resistance. [ 8 ] [ 9 ]


The human body stores its genetic information in  chromosomes . The number of chromosomes and the  gene locus  on the chromosome is unique to each species. Humans have 23 pairs of chromosomes, 22 pairs of  autosomal chromosomes  and 1 pair of  sex chromosomes  that differentiate between males and females. [ 10 ]  All human chromosomes have 2 arms –  the p (short) and the q (long) arm , which are separated by the  centromeres . [ 11 ]


There are two proposed mechanisms of forming the ring chromosome. One suggests that chromosome 15 undergoes distortion on both p and q arms prior to the fusion of two broken arms, resulting in great loss of genetic materials. Therefore, the patients of this type of ring chromosome 15 display severe clinical features. [ 12 ]


The other proposed mechanism suggests the direct fusion of two  telomeres  without losing any of the telomeric and subtelomeric sequences. Consequently, most of the genetic material is conserved and symptoms are expressed in a milder form, making diagnosis more difficult. [ 13 ]


In most cases, postnatal diagnosis is done and up to 2011, only four cases are reported via prenatal diagnosis. [ 3 ]
Congenital diaphragmatic hernia and  intrauterine growth retardation  (these two signs put the patients at the risk of afflicting with ring chromosome 15) by fetal  ultrasound  ( Obstetric ultrasonography ) at the time period of 16–24 weeks, further investigation and diagnostics (such as karyotyping) must be performed to test the possibility of ring chromosome 15. [ citation needed ]


Patients could be considered to have ring chromosome 15 if they are found with: growth deficiency, [ 3 ]  café au lait spots, bone age delay, and  simian crease  or other dysmorphic features after birth. [ citation needed ]


Treatment of the disease is based on alleviating symptoms, [ 1 ]  commonly including  physiotherapy ,  occupational therapy , and  speech and language therapy . [ 14 ]  In addition, case reports have found that recombinant human growth hormone treatment may be beneficial for improving the  growth velocity  of patients with short stature. [ 3 ] [ 4 ] [ 15 ]


Ring chromosome syndromes are rare congenital disorders that are likely to occur in both males and females, and the symptoms can be observed from birth since it arises during the embryonic stage. All races and ethnicities are prone to the disorders and the risk can be higher if the parents are carriers since it is genetically inherited. [ citation needed ]


Any of the 23 pairs of chromosomes can be ringed, and a recent study conducted by the 'Human Ring Chromosome Registry' in China revealed that the more frequent forms of ring chromosomes reported were 13, 15, 18, and 22. [ 16 ]


Ring chromosome 15 is an uncommon genetic disorder first noted by Dr. Petrea Jacobsen in 1966. [ 17 ]  As of 2005, less than 50 cases have been reported. [ 2 ]


Rosselli–Gulienetti syndrome , [ 2 ]  also known as  Zlotogora–Ogur syndrome [ 3 ]  and  Bowen–Armstrong syndrome , [ 4 ]  is a type of  congenital   ectodermal dysplasia   syndrome . The syndrome is relatively rare [ 5 ]  and has only been described in a few cases.


There is a range of signs and symptoms including  cleft lip  or  palate ,  intellectual disabilities  and various forms of  ectodermal dysplasia . Additional symptoms may include  fused eyelids ,  absent nails ,  delayed bone growth  and  dry skin . It is believed that this syndrome follows an  autosomal   dominant  pattern of inheritance with  incomplete penetrance , [ 5 ]  and caused by a  mutation  affecting the  TP63  gene. [ 6 ]  It has been suggested that this syndrome,  AEC syndrome  and  Rapp–Hodgkin syndrome  may be variations of the same disease. [ 7 ]


It is not uncommon for heterozygotes for the condition (especially those originating from  Margarita Island ) to have a broad and flat  philtrum . [ 8 ]


It is caused by mutations in the gene PVRL1 (11q23-q24) which encodes nectin-1, the principal receptor used by alpha-herpesviruses to mediate entry into human cells. Although the mechanism underlying the physiopathology of this syndrome is still unknown, it has been proposed that nectin-1 is a cell-cell adhesion molecule that is preferentially expressed in keratinocytes and that mutations in PVRL1 may abrogate NAP (nectin, afadin, ponsin)-dependent cell-cell adhesion. It is thought that the genetic transmission is autosomal recessive gene transmission.[8]


The cause was found in the year 2000 by Suzuki et al. when he  analyzed the genome  of patients with the disorder and discovered a homozygous  nonsense mutation  in the  PVRL1  gene, in  chromosome 11 . It was suggested that the regular occurrence of this disorder among the people of  Margarita Island  was due to resistance to alpha-herpes viruses people carrying only one copy of the mutated gene (heterozygosity) had. The same mutation in the same gene was found in two families from the Middle East and South America ( Israel  and  Brazil  respectively.) by the same researchers (Suzuki et al.)


Diagnosis is usually done by  genetic testing . [ citation needed ]


There is no specific treatment or cure for individuals affected with this type of syndrome, though some of the abnormal physical features may be surgically correctable. [ 4 ]


About 35 cases have been described in medical literature. [ 9 ] [ verification needed ]


In  Margarita Island ,  Venezuela , it is estimated that 1 out of every 22 people carry one copy of the Rosselli-Gulienitti-causing mutation, while 5 out of every 1,000 live births in the same island are born with the disease itself. [ 10 ]


Rubinstein–Taybi syndrome  ( RTS ) is a rare genetic  condition  characterized by short stature, moderate to severe learning difficulties, distinctive facial features, and broad thumbs and first toes. [ 2 ]  Other features of the disorder vary among affected individuals. These characteristics are caused by a mutation or deletion in the  CREBBP  gene, located on chromosome 16, and/or the  EP300  gene, located on chromosome 22. [ 3 ]


This condition is sometimes inherited as an  autosomal dominant  pattern, but often as a de novo. It affects an estimated 1 in 125,000-300,000 births.


Rubinstein–Taybi syndrome presents itself from birth, and is usually hallmarked by delayed physical and cognitive growth. [ citation needed ]


Typical features of the disorder include:


A 2009 study found that children with RTS were more likely to be overweight and to have a short  attention span , motor  stereotypies , and poor coordination. The study hypothesized that the identified CREBBP gene impaired motor skills learning. [ 8 ]  Other research has shown a link with long-term memory (LTM) deficit. [ 9 ] [ 10 ]


RTS is diagnosed when a  heterozygous pathogenic variant  of the CREBBP gene is identified in the individual. It exhibits an  autosomal dominant  inheritance pattern, but some documented cases show heterozygous individuals exhibiting  germline mosaicism . This condition affects men and women equally, and is often misdiagnosed with other diseases or disabilities that result in delayed mental development. [ citation needed ]


Rubinstein–Taybi syndrome, in many cases, is a  microdeletion syndrome  involving chromosomal segment 16p13.3 and is characterized by  mutations  in the  CREBBP   gene . [ 11 ] [ 12 ]  Varying amounts of material are deleted from this section of the chromosome and account for the spectrum of physiological symptoms. [ 13 ]


The  CREBBP  gene makes a protein that helps control the activity of many other genes. The protein, called  CREB-binding protein , plays an important role in regulating  cell growth  and  division  and is essential for normal  fetal development . If one copy of the  CREBBP  gene is deleted or mutated, cells make only half of the normal amount of CREB binding protein. A reduction in the amount of this protein disrupts normal development before and after birth, leading to the signs and symptoms of Rubinstein–Taybi syndrome. [ 14 ]


Mutations in the  EP300  gene, located on chromosome 22q13.2, are responsible for a small percentage of cases of Rubinstein–Taybi syndrome. [ 3 ]   These mutations result in the loss of one copy of the gene in each cell, which reduces the amount of p300 protein by half. Some mutations lead to the production of a very short, nonfunctional version of the p300 protein, while others prevent one copy of the gene from making any protein at all. Although researchers do not know how a reduction in the amount of p300 protein leads to the specific features of Rubinstein–Taybi syndrome, it is clear that the loss of one copy of the EP300 gene disrupts normal development. [ citation needed ]


CREBBP and p300 are the respective protein products of the  paralogous  genes  CREBBP  and  EP300 .  Both of these related proteins, prototypical members of the  p300-CBP coactivator family , have a  bromodomain  and a  histone acetyltransferase  domain and are able to bind to various gene-specific  transcription factors  as well as  general transcription factors . [ 15 ]   Cell lines derived from RTS patients exhibit diminished acetylation of multiple  histone  proteins, particularly histone 2A and histone 2B, [ 16 ]  suggesting that this disease has its origins in problems with the regulatory mechanisms of  transcription . [ 17 ]   The functions of CREBBP and p300 broadly overlap but do have co-activator–specific effects on gene expression. [ 18 ]   The proteins may also facilitate  transcriptional elongation . [ 19 ]


In approximately one third of the cases showing RTS symptoms, neither the   CREBBP  gene, nor the  EP300  gene appear to be the cause of the disease. [ 3 ]


A mouse  model  has been identified in order to perform experimental research procedures. The mice exhibited the same clinical RTS symptoms seen in humans, and the  model  has become a foundation for future research. [ 20 ]


There is no existing treatment that reverses or cures RTS. There are, however, ways to manage and reduce symptoms for patients. Due to there being a wide range of symptoms, RTS patients are referred to specialists that focus on each specific symptom. Individuals suffering from cognitive developments usually are part of special education programs and speech therapy. Regular check-ups and monitoring are needed for cardiac, dental, auditory, and renal abnormalities.  Genetic counseling  is also recommended for affected individuals and their families. [ 21 ]


Rubinstein–Taybi syndrome was first unofficially mentioned in a French orthopedic medical journal in 1957 by Greek physicians' doctors:  Michail, Matsoukas, and Theodorou . The medical journal reported a case concerning a seven-year-old boy with radically deviated/arched thumbs, long nose,  muscular hypotonia , along with physical and mental underdevelopment. At this point in time the case study mentioned by the Greek physicians was considered to be an anomaly due to the fact that there hadn't been any other reported cases of children with these specific physical and mental characteristics. The doctors accredited with discovering the syndrome and therefore bear its name-sake were unaware of this journal at the time of their discovery. However, it is acknowledged that the 1957 case reported in the French journal of orthopedic medicine is most likely the first reported case of RTS. [ citation needed ]


Dr. Jack Herbert Rubinstein, an American pediatrician reported assessing a three-year-old girl with unusual facial and digital findings in 1958. Similarly, that same year Rubinstein had evaluated another child with similar characteristics, this time a seven-year-old boy. Having sensed a striking similarity between these two unrelated cases Rubinstein tried distributing photos and information concerning these two cases to other clinics in the U.S. from 1959 to 1960. Rubinstein graduated from Harvard Medical School and worked as the director of the Hamilton County Diagnostic Clinic for the Mentally Retarded. He has worked in behavioral and developmental pediatrics for many years prior to the discovery of this new syndrome. [ citation needed ]


In 1961,  Dr. Hooshang Taybi , an Iranian-American pediatric radiologist, reported having assessed a three-year-old boy that appeared to have the same syndrome as described by Rubinstein. During the summer of 1963 Dr. Taybi reported having evaluated seven children with characteristics such as broad thumbs and great toes, "unusual" facial features, and intellectual disabilities – these findings went on to appear in the  American Journal of Diseases of Children  documenting these characteristics as a syndrome. Dr. Hooshang Taybi graduated from Tehran University School of Medicine and worked for the Ministry of Health. Later in his career he taught and practiced pediatric radiology in Oklahoma and Indiana. He had identified three new syndromes with his colleagues, among them is Rubinstein–Taybi syndrome. [ citation needed ]


In 1992 the first genetic abnormalities that act as markers for Rubinstein-Taybi syndrome were identified. These abnormalities are said to affect either  chromosome 16  or  chromosome 22 . The specific chromosome impacted by a mutation determines the type of Rubinstein–Taybi syndrome that may occur. A mutation of the  CREBBP  gene  on chromosome 16 gives rise to the first form of RTS (most common). While a mutation of the  EP300  gene  on chromosome 22 is characteristic of the second form of RTS. [ citation needed ]


Rudiger syndrome  is a  congenital disorder  characterized by the association of severe growth retardation with abnormalities of the extremities, urogenital abnormalities and facial abnormalities. [ 1 ]  It has been described in a family where an affected brother and sister died as infants. [ 2 ]  Both  autosomal   recessive  and autosomal  dominant  inheritance have been suggested with the disorder. [ 1 ] [ 3 ]


The features  ectrodactyly ,  ectodermal dysplasia  and  cleft palate  have been described with Rudiger syndrome, giving it the rarely used designation "EEC syndrome". [ 3 ]  However, this is not to be confused with the formal  EEC syndrome  associated with  chromosome 7 . [ 4 ]


It was characterized in 1971. [ 5 ]


A  sacral dimple  (also termed  pilonidal dimple  or  spinal dimple ) [ 1 ]  is a small depression in the skin, located just above the  buttocks . [ 2 ] [ 3 ] [ 4 ] [ 5 ]  The name comes from the  sacrum , the bone at the end of the spine, over which the  dimples  are found.  A sacral dimple is defined as a midline dimple less than 5 mm in diameter and no further than 2.5 cm from the anus without associated visible drainage or hairy tuft. [ 6 ]


Sacral dimples are common  benign congenital anomalies  found in up to 4% of the population. [ 1 ] [ 5 ]   [ 6 ]  Other common benign congenital anomalies include supernumerary digits, third nipples and natal teeth.  [ 7 ]   Most sacral dimple cases are minor and do not relate to any underlying medical problem, [ 1 ] [ 3 ] [ 5 ]  but some can result from disease, notably  spina bifida . [ 3 ] [ 5 ]  If so, this is usually the  spina bifida occulta  form, which is the least serious kind. [ 3 ]


Simple dimples are typically small, measuring less than 5 mm in size. They are positioned in the midline, within 2.5 cm of the anus, and do not have any other associated skin abnormalities. Atypical dimples, on the other hand, have different characteristics. They are larger than 5 mm in size and are located within 25 mm of the anus. Atypical dimples can also be deep, positioned above the gluteal crease, located outside the midline, or occur as multiple dimples. [ 8 ]


Sacral dimples are often spotted in post-natal checks by  pediatricians , [ 3 ] [ 5 ]  who can check:


For clinicians dealing with infants who have sacral dimples, it is essential to be aware of the characteristics of atypical dimples. Careful examinations should be conducted to identify any atypical features in order to appropriately manage and refer these cases in clinical practice.
Understanding the distinction between simple and atypical sacral dimples is crucial for pediatric practitioners because of the potential association with occult spinal dysraphism (OSD). The pooled incidence of OSD in patients with an atypical dimple, as observed in several studies, was significantly higher (8.8%) compared to patients with a simple dimple (0.6%). Given this increased risk, infants with atypical dimples require further evaluation through radiologic imaging and early referrals to neurosurgical specialists. Prompt identification and appropriate management of atypical dimples can help ensure timely intervention and improved outcomes for infants with potential underlying spinal abnormalities.  [ 8 ]


A sacral dimple could also indicate a  kidney  problem of a kind that can be checked with an  ultrasound . [ citation needed ]


Sacral dimples were selected for one study by the  ICD9CM  code of 685.1. [ 3 ]


Sacrococcygeal teratoma  ( SCT ) is a type of tumor known as a  teratoma  that develops at the base of the  coccyx  (tailbone) and is thought to be primarily derived from remnants of the  primitive streak . [ 1 ]  Sacrococcygeal teratomas are  benign  75% of the time,  malignant  12% of the time, and the remainder are considered "immature teratomas" that share benign and malignant features. Benign sacrococcygeal teratomas are more likely to develop in younger children who are less than 5 months old, and older children are more likely to develop malignant sacrococcygeal teratomas.


The  Currarino syndrome , due to an  autosomal dominant  mutation in the  MNX1  gene, consists of a presacral mass (usually a mature teratoma or anterior meningocele), anorectal malformation and sacral dysgenesis.


Maternal complications of pregnancy may include  mirror syndrome . [ 2 ]   Maternal complications of delivery may include a  cesarean section  or, alternatively, a vaginal delivery with mechanical  dystocia . [ 3 ]


Complications of the mass effect of a teratoma in general are addressed on the  teratoma  page.  Complications of the mass effect of a large SCT may include  hip dysplasia ,  bowel obstruction ,  urinary obstruction ,  hydronephrosis  and  hydrops fetalis .  Even a small SCT can produce complications of mass effect, if it is presacral (Altman Type IV). [ 4 ]   In the fetus, severe hydronephrosis may contribute to inadequate lung development.  Also in the fetus and newborn, the  anus  may be  imperforate . [ citation needed ]


Later complications of the mass effect and/or surgery may include  neurogenic bladder , other forms of  urinary incontinence ,  fecal incontinence , and other chronic problems resulting from accidental damage to or sacrifice of nerves and muscles within the pelvis. [ 5 ]   Removal of the coccyx  may include additional complications. In one review of 25 patients, [ 6 ]  however, the most frequent complication was an unsatisfactory appearance of the surgical scar.


Late effects are of two kinds:  consequences of the tumor itself, and consequences of surgery and other treatments for the tumor. [ citation needed ]


Complications of not removing the coccyx may include both recurrence of the teratoma [ 7 ]  and  metastatic cancer . [ 7 ] [ 8 ]   Late malignancies usually involve incomplete excision of the coccyx and are  adenocarcinoma . [ citation needed ] Although functional disability in survivors is common, [ 9 ]  a small comparative study [ 10 ]  found a nonsignificant difference between SCT survivors and a matched control group.


In rare cases, pelvic scarring may necessitate that a  pregnant woman  who is a SCT survivor deliver her baby by  cesarean section . [ 11 ]


SCT is seen in 1 in every 35,000 live births, and is the most common tumor  presenting  in newborn humans.  Most SCTs are found in babies and children, but SCTs have been reported in adults [ 12 ]  and the increasingly routine use of prenatal ultrasound exams has dramatically increased the number of diagnosed SCTs presenting in fetuses.  Like other teratomas, an SCT can grow very large.  Unlike other teratomas, an SCT sometimes grows larger than the rest of the fetus. [ citation needed ]


Sacrococcygeal teratomas are the most common type of  germ cell tumors  (both  benign  and  malignant ) diagnosed in  neonates ,  infants , and  children  younger than 4 years. [ 13 ]   SCTs occur more often in girls than in boys; ratios of 3:1 to 4:1 have been reported. [ 14 ]


Historically, sacrococcygeal teratomas present in 2 clinical patterns related to the child's age, tumor location, and likelihood of tumor malignancy.  With the advent of routine prenatal ultrasound examinations, a third clinical pattern is emerging. [ citation needed ]


During  prenatal ultrasound , an SCT having an external component may appear as a fluid-filled cyst or a solid mass sticking out from the fetus' body.  Fetal SCTs that are entirely internal may be undetected if they are small;  detection (or at least suspicion) is possible when the fetal bladder is seen in an abnormal position, due to the SCT pushing other organs out of place. [ citation needed ]


At  birth , the usual presentation is a visible lump or mass under the skin at the top of the buttocks crease.  If not visible, it can sometimes be felt; gently prodded, it feels somewhat like a hardboiled egg.  A small SCT, if it is entirely inside the body, may not present for years, until it grows large enough to cause pain, constipation and other symptoms of a large mass inside the  pelvis , or until it begins to extend out of the pelvis.  Even a relatively large SCT may be missed, if it is internal, because the bony  pelvis  conceals and protects it.   Mediastinal tumors , including teratomas, are similarly concealed and protected by the  rib cage . [ citation needed ]


Some SCTs are discovered when a child begins to talk at about age 2 years and complains of their bottom hurting or feeling "poopy" when they ride in a car seat.


Other tumors can occur in the sacrococcygeal and/or presacral regions [ 16 ]  and hence must be ruled out to obtain a  differential diagnosis .  These include  extraspinal ependymoma , [ 17 ]   ependymoblastoma , [ 18 ]   neuroblastoma  and  rhabdomyosarcoma .


Smaller SCTs with an external component, seen in prenatal ultrasounds or at birth, often are mistaken for  spina bifida . [ citation needed ]   Cystic SCT and terminal myelocystocele are especially difficult to distinguish;  for more accurate diagnosis, MRI has been recommended. [ 19 ]


The preferred first treatment for SCT is complete surgical removal (i.e., complete resection). The preferred approach to a small SCT is through the  perineum ; a large SCT may require an additional approach through the  abdomen .  Resection should include the coccyx and may also include portions of the  sacrum . The surgery should include reattachment of the small muscles and ligaments formerly attached to the coccyx, in effect reconstructing the posterior perineum.  If not, there is an increased risk of  perineal hernia  later in life. [ citation needed ]


SCTs are classified morphologically according to their relative extent outside and inside the body: [ citation needed ]


The Altman type is significant in the contexts of management of labor and delivery, surgical approach, and complications of SCT.  Serial ultrasound and MRI monitoring of SCTs in fetuses  in utero  has demonstrated that the Altman type can change over time.  As the tumor grows, it can push between other organs and through the perineum to the body surface where the tumor appears as a bulge covered only by skin.  Sometimes, the tumor bulge later slips back inside the perineum. [ citation needed ]


Like all  teratomas , a sacrococcygeal teratoma has the potential to be  malignant , and the standard of care requires long-term followup by an  oncologist .


Management of most fetal SCTs involves  watchful waiting  prior to any treatment.  An often used  decision tree  is as follows: [ citation needed ]


Emergent problems include maternal  mirror syndrome ,  polyhydramnios , and  preterm labor .  Poor management decisions, including interventions that are either premature or delayed, can have dire consequences. [ 20 ] [ 21 ]   A very small retrospective study of 9 babies with SCTs greater than 10 cm diameter reported slightly higher survivorship in babies remaining in utero slightly longer. [ 22 ]


In many cases, a fetus with a small SCT (under 5 or 10 cm) may be delivered vaginally. [ 23 ] [ 24 ] [ 25 ] [ 26 ]  Prior to the advent of prenatal detection and hence scheduled C-section, 90% of babies diagnosed with SCT were born full term. [ 27 ]


SCTs are very rare in adults, and as a rule these tumors are benign and have extremely low potential for malignancy.  This estimation of potential is based on the idea that because the tumor existed for decades prior to diagnosis, without becoming malignant, it has little or no potential to ever become malignant.  For this reason, and because  coccygectomy in adults has greater risks than in babies , some surgeons prefer not to remove the coccyx of adult survivors of SCT.  There are case reports of good outcomes. [ 28 ]


Saethre–Chotzen syndrome  ( SCS ), also known as  acrocephalosyndactyly type III , is a rare  congenital disorder  associated with  craniosynostosis  (premature closure of one or more of the sutures between the bones of the  skull ). This affects the shape of the head and face, resulting in a cone-shaped head and an asymmetrical face. Individuals with SCS also have droopy eyelids ( ptosis ), widely spaced eyes ( hypertelorism ), and minor abnormalities of the hands and feet ( syndactyly ). [ 2 ]  Individuals with more severe cases of SCS may have mild to moderate intellectual or learning disabilities. Depending on the level of severity, some individuals with SCS may require some form of medical or surgical intervention. [ 3 ]  Most individuals with SCS live fairly normal lives, regardless of whether medical treatment is needed or not. [ 2 ]


SCS presents in a variable fashion. The majority of individuals with SCS are moderately affected, with uneven facial features and a relatively flat face due to underdeveloped eye sockets, cheekbones, and lower jaw. In addition to the physical abnormalities, people with SCS also experience growth delays, which results in a relatively short stature. Although, most individuals with SCS are of normal intelligence, some individuals may have mild to moderate  mental delays . More severe cases of SCS, with more serious facial deformities, occurs when multiple cranial sutures close prematurely. [ 2 ]


The cranium consists of three main sections including the base of the cranium ( occipital bone ), the face ( frontal bone ), and the top ( parietal bones ) and sides ( temporal bone ) of the head. Most of the bones of the cranium are permanently set into place prior to birth. However, the temporal and parietal bones are separated by  sutures , which remain open, allowing the head to slightly change in shape during childbirth. The cranial sutures eventually close within the first couple of years following birth, after the brain has finished growing. [ 2 ]


In individuals with SCS, the coronal suture separating the frontal bones from the parietal bones, closes prematurely ( craniosynostosis ), occasionally even before birth. If the coronal suture closes asymmetrically or unilaterally, then the face and forehead will form unevenly, from side-to-side. People with SCS have pointy, tower-like heads because their brain is growing faster than their skull, resulting in increased intracranial pressure (ICP) and causing the top of the head and/or forehead to bulge out to allow for brain growth. The face appears uneven, particularly in the areas of the eyes and cheeks, and the forehead appears wide and tall. [ 2 ]


Because of the abnormal forehead, there is less space for the normal facial features to develop. This results in shallow eye sockets and flat cheekbones. The shallow eye sockets make the eyes more prominent or bulging and cause the eyes to be more separated than normal (hypertelorism). The underdeveloped eye sockets, cheekbones, and lower jaw cause the face to appear flat. Furthermore, the minor downward slant of the eyes along with the drooping eyelids ( ptosis ) adds to the overall unevenness of the face. [ 2 ]


SCS is typically inherited as an  autosomal dominant  trait. However, on occasion, children with a  microdeletion  of 7p21 (chromosome containing the  locus  responsible for SCS) develop new abnormalities and typically show significant neurological abnormalities. An increased parental age may play a role in the development of new mutations and abnormalities. [ 3 ]


Linkage analysis  and  chromosomal rearrangement  revealed the cause of SCS to be mutations in the  TWIST  gene (twist transcription factor gene) located on chromosome 7p21. The TWIST gene encodes a  basic helix-loop-helix  (b-HLH)  transcription factor  that controls head  mesenchyme  development as the cranial tube forms. More than 35 varying TWIST mutations involving the b-HLH domain of the protein have been identified in people with SCS. The mutations include  missense ,  nonsense , and  frameshift   deletion / insertion  mutations that either shorten or disrupt the b-HLH domain. Most individuals with SCS have a single large deletion in the region 7p21, which contains the region that codes for the TWIST gene. [ 6 ]


In searching for the gene responsible for SCS, scientists at Johns Hopkins Children's Center began studying the TWIST gene because its effects on mice. The TWIST gene in mice, functions in the development of the muscle and skeleton of the face, head, hands, and feet. Mice that were lacking both copies of the TWIST gene were spontaneously aborted prior to birth, and had serious deformities including abnormal limb and head defects and failure of the  neural tube  to properly close. However, mice with a single copy of the non-working TWIST gene survived. Further examination revealed that these mice had only minor skull, hand, and foot defects similar to those seen in SCS. The mouse TWIST gene is located on chromosome 12 in mice, which corresponds to the short arm of  chromosome 7  in humans. With this information, scientists began to isolate and  map  the human TWIST gene on the short arm of human chromosome 7. They revealed that the human TWIST gene was in the same region that was absent in people with SCS. While looking for different mutations in the human TWIST gene, five different types of mutations were discovered in individuals with SCS. Since none of these mutations were seen in normal individuals who didn't have SCS, this provided enough evidence to conclude that the TWIST gene was the causative agent of SCS1. Researchers also studied the TWIST gene in  Drosophila  (fruit fly) in order to determine its function. They discovered that in the presence of two TWIST protein molecules combined together, the TWIST gene functions as a DNA transcription factor, meaning it binds to the  DNA double-helix  at specific locations in order to control which genes are "turned on" or activated. The majority of the identified mutations in the TWIST gene interfere with how the protein attaches to DNA, preventing the activation of other genes that would normally be turned on during fetal development. [ 2 ]


Prenatal diagnosis  of Saethre-Chotzen Syndrome in high risk pregnancies is doable, but very uncommon and rarely performed. Furthermore, this is only possible if the  mutation  causing the disease has already been identified within the family  genome . There are a few different techniques in which prenatal testing can be carried out.  Prenatal testing is usually performed around 15–18 weeks, using  amniocentesis  to extract  DNA  from the fetus's cells. Prenatal testing can also be performed during weeks 10–12 using  chorionic villus sampling (CVS)  to extract DNA from the fetus. [ 7 ]  Recently, there has been an increased interest in utilizing  ultrasound  equipment in order to detect fetal skull abnormalities due to immature fusion of the  cranial sutures . [ 4 ]


The overall diagnosis of SCS is primarily based on clinical findings and observations based on  dysmorphology  examination (assessing structural defects) and radiographic evaluation ( X-rays ,  MRIs , and  CT scans ). [ 6 ]


A clinical diagnosis of SCS can be verified by testing the  TWIST1  gene (only  gene  in which  mutations  are known to cause SCS) for mutations using DNA analysis, such as  sequence analysis ,  deletion / duplication  analysis, and  cytogenetics /  FISH  analysis. Sequence analysis of  exon  1 (TWIST1  coding region ) provides a good method for detecting the frequency of mutations in the TWIST1 gene. These mutations include  nonsense ,  missense ,  splice site mutation , and intragenic  deletions / insertions . Deletion/duplication analysis identifies mutations in the TWIST1 gene that are not readily detected by sequence analysis. Common methods include  PCR ,  multiplex ligation-dependent probe amplification (MLPA) , and  chromosomal microarray (CMA) . Cytogenetic/FISH analysis attaches fluorescently labels DNA markers to a denatured  chromosome  and is then examined under fluorescent lighting, which reveals mutations caused by  translocations  or  inversions  involving 7p21. Occasionally, individuals with SCS have a chromosome translocation, inversion, or  ring chromosome  7 involving 7p21 resulting in atypical findings, such as, increased developmental delay. [ 7 ]  Individuals with SCS, typically have normal brain functioning and rarely have mental impairments. For this reason, if an individual has both SCS and  mental retardation , then they should have their TWIST1 gene screened more carefully because this is not a normal trait of SCS. [ 2 ]   Cytogenetic testing  and  direct gene testing  can also be used to study gene/chromosome defects. Cytogenetic testing is the study of chromosomes to detect gains or losses of chromosomes or chromosome segments using fluorescent in situ hybridization (FISH) and/or  comparative genomic hybridization (CGH) . Direct gene testing uses blood, hair, skin,  amniotic fluid , or other tissues in order to find  genetic disorders . Direct gene testing can determine whether an individual has SCS by testing the individual's blood for mutations in the TWIST1 gene. [ 7 ]


Genetic testing allows for a definitive diagnosis because it allows similar conditions to be differentiated from each other based on which gene is mutated. [ 2 ]  The following table contains conditions similar to SCS:


The physical abnormalities resulting from SCS are typically mild and only require a minor surgical procedure or no procedure at all. One of the common symptoms of SCS is the development of short ( brachydactyly ), webbed fingers and broad toes ( syndactyly ). These characteristics do not cause any problems to the function of the hands or feet, and thus, no medical procedure is required to fix the abnormalities, unless the patient requests it. Webbing of the fingers may affect the base of the fingers, resulting in delayed hand growth during childhood, but this contributes no functional impairments. Sometimes, individuals with SCS develop broad toes because the bones at the ends of the toes are duplicating themselves. This is especially seen in the big toe, but requires no surgical intervention because it doesn't negatively affect the overall function of the foot. Individuals with these toe abnormalities walk normally and can wear normal footwear. [ 9 ]


In more severe cases, frequent surgeries and clinical monitoring are required throughout development. A child born with asymmetrical unilateral coronal  synostosis  should undergo  cranioplasty  within its first year of life in order to prevent increased  intracranial pressure  and to prevent progressive  facial asymmetry . Cranioplasty is a surgical procedure to correct prematurely fused cranial bones. The surgery acts to reconstruct and reposition the bones and sutures in order to promote the most normal growth. [ 6 ]  Cranioplasty is necessary in order to continue to grow and is important for two main reasons. First of all, the  skull  needs to be able to accommodate the growing brain following childbirth, which it can't because the skull doesn't grow as fast as the brain as long as the  sutures  remain fused. This results in an increase in pressure surrounding the brain and inhibits the brain from growing, causing the individual to experience significant problems, and if left untreated can eventually lead to death. Secondly, cranioplasty may be required for appearance purposes. [ 7 ]  This is especially the case in individuals with asymmetrical unilateral coronal synostosis, which requires  reconstructive surgery  of the face and skull. If cranioplasty is not performed, especially in individuals with unilateral coronal synostosis, then facial asymmetry will get worse and worse over time, which is why cranioplasty should be performed as soon as possible. [ 9 ]


Surgery may also be required in individuals with vision problems. Vision problems usually arise due to a lack of space in the eye orbit and skull because of the abnormal bone structure of the face. Decreased space may also lead to abnormal or missing  tear ducts  and nerve damage. Reconstructive surgery is usually required in order to increase cranial space, correct tear duct  stenosis , and/or correct  ptosis  of the eyelids in order to prevent  amblyopia  (lazy eye). [ 2 ]


Midfacial surgery may also be required during early childhood to correct respiratory problems,  dental malocclusion , and swallowing difficulties. A  cleft palate  is also corrected with surgery, and may involve the use of  tympanostomy tubes . If needed, an individual will undergo  orthognathic treatment  and/or orthodontic treatment after facial development is complete. [ 2 ]  Since hearing loss is frequently associated with SCS, it is recommended that audiology screening persist throughout childhood. [ 6 ]


After cranial reconstructive surgery, a child may be required to wear a molding helmet or some other form of head protection until the cranial bones set into place. This typically takes about three months and depends on the child's age and the severity of the condition. Following recovery, individuals with SCS look and act completely normal, so no one would even be able to tell that they have SCS. [ 10 ]


SCS is the most common  craniosynostosis  syndrome and affects 1 in every 25,000 to 50,000 individuals. [ 11 ]  It occurs in all racial and ethnic groups, and affects males and females equally. [ 2 ]  If a parent carries a copy of the SCS gene mutation, then there is a 50% chance their child will also carry a copy of the gene mutation, in which case, the child may or may not show signs of SCS. There is also a 50% chance their child will have two working copies of the gene, and would therefore, not have SCS. If both parents carry a single copy of the SCS gene mutation, then there is a 25% chance their child will have two gene mutation copies (so child would develop severe SCS), a 25% chance their child would have two normal copies of the gene (so would be completely normal), and a 50% chance their child would carry one gene mutation copy and 1 normal copy (so child may or may not display SCS). [ 2 ]  In rare situations, two normal parents can have a child with SCS due to a  de novo  mutation . The exact cause of the  de novo  mutation is unknown, but it doesn't seem to be related to anything that the parents did or didn't do during the pregnancy. [ 12 ]  SCS due to a  de novo  mutation is so rare that the proportion of past cases is unknown. [ 7 ]


In 1931, Haakon Saethre, a Norwegian  psychiatrist , described similar characteristics between a mother and her two daughters. They all had long and uneven facial features, low-set hairlines, short fingers, and webbing between the second and third fingers and between the second, third, and fourth toes. A year later in 1932, F. Chotzen, a German  psychiatrist , described a father and his two sons as having very similar characteristics as the mother and her daughters, as well as having hearing loss, short stature, and mild mental retardation. Hence, the name Saethre-Chotzen Syndrome was derived from the two scientists, who had separately described the condition without any previous knowledge of the other. [ 2 ]


Seckel syndrome , or  microcephalic  primordial dwarfism  (also known as  bird-headed dwarfism ,  Harper's syndrome ,  Virchow–Seckel dwarfism  and  bird-headed dwarf of Seckel [ 1 ] ) is an extremely rare  congenital   nanosomic  disorder. Inheritance is  autosomal recessive . [ 2 ]  It is characterized by  intrauterine growth restriction  and postnatal  dwarfism  with a  small head , narrow bird-like face with a beak-like nose, large eyes with down-slanting  palpebral fissures , [ 3 ]  receding  mandible  and  intellectual disability .


A mouse model has been developed. [ 4 ]  This mouse model is characterized by a severe deficiency of  ATR  protein. [ 4 ]  These mice have high levels of replicative stress and  DNA damage . Adult Seckel mice display accelerated aging. [ 4 ]  These findings are consistent with the  DNA damage theory of aging .


Symptoms include: [ 5 ]


It is believed to be caused by defects of genes on  chromosome   3  and  18 . One form of Seckel syndrome can be caused by mutation in the gene encoding the  ataxia telangiectasia and Rad3-related  protein ( ATR ) which maps to chromosome 3q22.1–q24. This gene is central in the cell's DNA damage response and repair mechanism.


Types include: [ 6 ]


There are 4 criteria for diagnosis: [ 7 ]


Other abnormalities can be a supportive criteria, such as: anemia, pancytopenia, cleft lip/palate scoliosis or kyphoscoliosis. [ 8 ]


Genetic testing can confirm diagnosis. [ 5 ]


There is no cure for Seckel syndrome. Symptomatic treatment is available. [ 9 ] [ 10 ]


The syndrome was named after German–American physician  Helmut Paul George Seckel [ 11 ]  (1900–1960). The synonym Harper's syndrome was named after pediatrician  Rita G. Harper . [ 12 ] [ 13 ]


Senior–Løken syndrome  is a  congenital   eye  disorder, first characterized in 1961. [ 1 ] [ 2 ] [ 3 ]   It is a rare,  ciliopathic ,  autosomal recessive  disorder characterized by  juvenile nephronophthis  and progressive  eye disease . [ 4 ]


Genes  involved include:


The cause of Senior–Løken syndrome type 5 has been identified to mutation in the NPHP1 gene which adversely affects the protein formation mechanism of the  cilia . [ 6 ]


Recent findings in genetic research have suggested that a large number of  genetic disorders , both  genetic syndromes  and  genetic diseases , that were not previously identified in the medical literature as related, may be, in fact, highly related in the  genetypical  root cause of the widely varying,  phenotypically -observed  disorders .  Such diseases are becoming known as  ciliopathies .  Known ciliopathies include  primary ciliary dyskinesia ,  Bardet–Biedl syndrome ,  polycystic kidney  and  liver disease ,  nephronophthisis ,  Alström syndrome ,  Meckel–Gruber syndrome  and some forms of  retinal degeneration . [ 4 ]


Sepiapterin reductase deficiency  is an inherited pediatric disorder characterized by movement problems, and most commonly displayed as a pattern of involuntary sustained muscle contractions known as  dystonia . Symptoms are usually present within the first year of age, but diagnosis is delayed due to physicians lack of awareness and the specialized diagnostic procedures. [ 2 ]  Individuals with this disorder also have delayed motor skills development including sitting, crawling, and need assistance when walking. Additional symptoms of this disorder include intellectual disability, excessive sleeping, mood swings, and an abnormally small head size. SR deficiency is a very rare condition. The first case was diagnosed in 2001, and since then there have been approximately 30 reported cases. At this time, the condition seems to be treatable, but the lack of overall awareness and the need for a series of atypical procedures used to diagnose this condition pose a dilemma. [ 3 ]


The oculogyric crises usually occur in the later half of the day and during these episodes patients undergo extreme agitation and irritability along with uncontrolled head and neck movements. Apart from the aforementioned symptoms, patients can also display  parkinsonism , sleep disturbances, small head size (microcephaly), behavioral abnormalities, weakness, drooling, and gastrointestinal symptoms. [ 4 ]


This disorder occurs through a mutation in the SPR gene, which is responsible for encoding the  sepiapterin reductase  enzyme. The enzyme is involved in the last step of producing  tetrahydrobiopterin , better known as BH 4 . BH 4  is involved in the processing of amino acids and the production of neurotransmitters, specifically that of  dopamine  and  serotonin  which are primarily used in transmission of signals between nerve cells in the brain. The mutation in the SPR gene interferes with the production of the enzyme by producing enzymes with little or no function at all. This interference results in a lack of BH 4  specifically in the brain. The lack of BH 4  only occurs in the brain because other parts of the body adapt and utilize alternate pathways for the production of BH 4 . The mutation in the SPR gene leads to nonfunctional sepiapterin reductase enzymes, which results in a lack of BH 4  and ultimately disrupts the production of dopamine and serotonin in the brain. [ 6 ]  The disruption of dopamine and serotonin production leads to the visible symptoms present in patients suffering from sepiapterin reductase deficiency. SR deficiency is considered an inherited  autosomal recessive  condition disorder because each parent carries one copy of the mutated gene, but typically do not show any signs or symptoms of the condition. [ 7 ]


The diagnosis of SR deficiency is based on the analysis of the  pterins  and  biogenic amines  found in the  cerebrospinal fluid  (CSF) of the brain. The pterin compound functions as a cofactor in enzyme catalysis and biogenic amines which include adrenaline, dopamine, and serotonin have functions that vary from the control of homeostasis to the management of cognitive tasks. [ 8 ]  This analysis reveals decreased concentrations of  homovanillic acid  (HVA),  5-hydroxyindolacetic acid  (HIAA), and elevated levels of  7,8-dihydrobiopterin , a compound produced in the synthesis of neurotransmitters. Sepiapterin is not detected by the regularly used methods applied in the investigation of biogenic monoamine metabolites in the cerebrospinal fluid. It must be determined by specialized methods that work by indicating a marked and abnormal increase of sepiapterin in cerebrospinal fluid. Confirmation of the diagnosis occurs by demonstrating high levels of CSF sepiapterin and a marked decrease of SR activity of the  fibroblasts  along with SPR gene molecular analysis. [ 2 ] [ 9 ]


SR deficiency is currently being treated using a combination therapy of levodopa and carbidopa. These treatments are also used for individuals suffering from Parkinson's. The treatment is noninvasive and only requires the patient to take oral tablets 3 or 4 times a day, where the dosage of  levodopa  and  carbidopa  is determined by the severity of the symptoms. Levodopa is in a class of medications called central nervous system agents where its main function is to become dopamine in the brain. Carbidopa is in a class of medications called decarboxylase inhibitors and it works by preventing levodopa from being broken down before it reaches the brain. This treatment is effective in mitigating motor symptoms, but it does not totally eradicate them and it is not as effective on cognitive problems. Patients who have been diagnosed with SR deficiency and have undergone this treatment have shown improvements with most motor impairments including oculogyric crises, dystonia, balance, and coordination. [ 9 ] [ 10 ]


The diagnosis of sepiapterin reductase deficiency in a patient at the age of 14 years was delayed by an earlier diagnosis of an initially unclassified form of  methylmalonic aciduria  at the age of 2. At that time the hypotonia and delayed development were not considered to be suggestive of a neurotransmitter defect. The clinically relevant diagnosis was only made following the onset of  dystonia  with diurnal variation, when the patient was a teenager. Variability in occurrence and severity of other symptoms of the condition, such as hypotonia,  ataxia , tremors, spasticity, bulbar involvement, oculogyric crises, and cognitive impairment, is comparable with autosomal dominant GTPCH and  tyrosine hydroxylase  deficiency, which are both classified as forms of DOPA-responsive dystonia. [ 11 ]


Hypotonia and Parkinsonism were present in two Turkish siblings, brother and sister. By using  exome sequencing , which sequences a selective coding region of the  genome , researchers have found a  homozygous  five- nucleotide  deletion in the SPR gene which confirmed both siblings were homozygous. It is predicted that this mutation leads to premature translational termination. Translation is the biological process through which proteins are manufactured. The homozygous mutation of the SPR gene in these two siblings exhibiting early-onset Parkinsonism showcases that SPR gene mutations can vary in combinations of clinical symptoms and movement. These differences result in a wider spectrum for the disease  phenotype  and increases the genetic  heterogeneity  causing difficulties in diagnosing the disease. [ 3 ]


This study examined the clinical history of the CSF and urine of two Greek siblings who were both diagnosed with SR deficiency. Both siblings displayed delayed psychomotor development and a movement disorder. The diagnosis was confirmed by measuring the SR enzyme activity and mutation analysis. The mutation analysis of the gene was performed using genomic DNA isolated from blood samples. The results concluded that both patients have low concentrations of HVA and HIAA and high concentrations of sepiapterin in the CSF, but neopterin and biopterin were abnormal in only one sibling. The results of this research indicates that when diagnosing the SR deficiency, the quantification of sepiapterin in the CSF is more important and indicative of SR deficiency than using  neopterin  and  biopterin  alone. The results also show that the urine concentrations of neurotransmitter metabolites are abnormal in patients with this disorder. This finding may provide an initial and easier indication of the deficiency before CSF analysis is performed. [ 12 ]


In medicine, a  sequence  is a series of ordered consequences due to a single cause. [ 1 ]


It differs from a  syndrome  in that seriality is more predictable: if A causes B, and B causes C, and C causes D, then D would not be seen if C is not seen. However, in less formal contexts, the term "syndrome" is sometimes used instead of sequence.Examples include:


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


-lipodystrophy-Rieger anomaly-diabetes syndrome
-Rieger anomaly-partial lipodystrophy syndrome


SHORT syndrome  is an uncommon autosomal-dominant condition marked by ocular depression, Rieger anomaly, teething delay, small height, hyperextensibility of joints, and/or hernias. It was characterized in 1975. [ 1 ]


The acronym SHORT, which stands for characteristic traits seen in the majority of patients, is incorporated into the name of the condition. These features include the following: [ 2 ]


Short stature. [ 2 ]


Hyperextensibility of the joints and/or inguinal hernias. [ 2 ]


Ocular depression. [ 2 ]


Rieger anomaly. [ 2 ]


Delayed teething. [ 2 ]


Additional clinical features include intrauterine growth restriction, facial dysmorphism (deep-set eyes, prominent forehead, hypoplastic or thin alae nasi, small chin, large low-set ears, border, and downturned mouth), wrinkled and thin skin emphasizing a progeroid appearance, and mild midface hypoplasia. [ 3 ]


Lipodystrophy, or the absence of adipose tissue beneath the skin, is another common characteristic of the condition that primarily affects the face, arms, and chest. The thin, transparent skin shows more blood vessels when there is insufficient adipose tissue. Progeria is the term for the appearance of premature aging in persons with the illness, who appear much older than their actual age. [ 2 ]


Diagnosis is based on facial characteristics and molecular  genetic testing  that will show a  mutation  on  gene  PIK3R1  (5q13.1) , which codifies the regulating alpha subunit of phosphatidylinositol 3-kinase. This mutation can alter the PI3K/AKT/mTOR signal route, which plays an important role in  cell growth  and  proliferation. [ citation needed ]


Treatment involves multiple disciplines.  [ citation needed ]


-Screening for insulin resistance during late childhood stage.


-Glucose intolerance and diabetes mellitus can be treated with a different diet and lifestyle changes.


-Regular eye checkups are recommended in order to keep vision.


-Dental anomalies can be treated with common methods (protheses, crown, etc.)


Shprintzen–Goldberg syndrome  is a  congenital  multiple-anomaly  syndrome  that has  craniosynostosis , multiple abdominal  hernias ,  cognitive impairment , and other skeletal malformations as key features. Several reports have linked the syndrome to a mutation in the  FBN1  gene, but these cases do not resemble those initially described in the medical literature in 1982 by Shprintzen and Goldberg, [ 2 ]  and Greally et al. in 1998 failed to find a causal link to  FBN1 . [ 3 ]  At this time, the cause of Shprintzen–Goldberg syndrome has been identified as a mutation in the gene  SKI  located on  chromosome 1  at the p36 locus. The syndrome is rare with fewer than 50 cases described in the medical literature to date. [ citation needed ]


People with Shprintzen-Goldberg syndrome can experience a range of symptoms that vary in severity. Due to  craniosynostosis , people with SGS may have a long and narrow head, wide spaced protruding eyes that may slant downwards, a high and narrow palate, a high and prominent forehead, a small lower jaw, and low-set posteriorly-rotated ears. Some other skeletal abnormalities people with SGS may experience include joint hypermobility,  clubfoot ,  scoliosis ,  camptodactyly ,  arachnodactyly , long limbs, and a chest which appears to sink in or stick out. Other symptoms that may be experienced include brain abnormalities (e.g., hydrocephalus ), developmental delays, intellectual disability, gastrointestinal problems (e.g., constipation,  gastroparesis , etc.), abdominal or umbilical hernias, easily bruised skin, trouble breathing, and  hypotonia . Some cardiac issues which are occasionally seen in people with SGS include  aortic aneurysm ,  aortic regurgitation , aortic root dilation,  mitral valve regurgitation , and  mitral valve prolapse . [ 4 ]


Simpson–Golabi–Behmel syndrome  ( SGBS ) is a rare inherited  congenital disorder  that can cause craniofacial, skeletal, vascular, cardiac, and renal abnormalities. There is a high prevalence of cancer associated in those with SGBS which includes wilms tumors, neuroblastoma, tumors of the adrenal gland, liver, lungs and abdominal organs.
The syndrome is inherited in an  X-linked recessive  manner. Females that possess one copy of the mutation are considered to be carriers of the syndrome but may still express varying degrees of the phenotype, suffering mild to severe malady. Males experience a higher likelihood of fetal death.


There are two types of SGBS, each associated with mutations on a different gene: [ citation needed ]


SGBS is also considered to be an  overgrowth syndrome  (OGS). OGS is characterized by a two to three standard deviation increase in weight, height, or head circumference above the average for sex and age.  One of the most noted features of OGS is the increased risk of  neoplasms  in certain OGSs. SGBS in particular has been found to have a 10% tumor predisposition frequency with 94% of cases occurring in the abdominal region, most being malignant. It is common for tumors to be embryonal in type and appear before the age of 10.
There are five different types of tumors that patients with SGBS might develop, all intra-abdominal:  Wilms tumor ,  hepatoblastoma ,  hepatocarcinoma ,  gonadoblastoma , and  neuroblastoma .
The most common types of tumors developed in patients are the Wilms tumor and hepatoblastoma. [ 2 ]


May include one or more of the following symptons: [ citation needed ]


Although not all causes of SGBS have been identified, one cause of SGBS type I is a mutation of the glypican-3 gene ( GPC3 ) on the X chromosome locus q26.1. This particular gene is widely expressed, especially in tissues derived from the  mesoderm  during fetal development. The function of this gene is to produce a protein that acts as a cell surface receptor that binds to transcription factors. Binding of the transcription factors allows regulation of cellular responses to growth factors such as members of the hedgehog protein family. When large or small deletions and missense mutations occur along the GPC3 gene, GPC3 can no longer negatively regulate Hedgehog signaling during development, therefore increasing cell proliferation and the risk of developing cancer. [ 3 ]  Limb patterning and skeletal development may also go awry when GPC3 mutations inhibit regulations of responses to bone morphogenetic proteins, another type of growth factor. [ 4 ]


It has been suggested that SGBS type II may be caused by duplication of the  GPC4  gene, which helps to regulate cell division and growth. [ 5 ]


Also, some patients diagnosed with SGBS do not have any  GPC3  or  GPC4  deletions or mutations. Possible explanations include promoter mutation or silencing of the  GPC3  gene causing reduced expression in these patients. [ 6 ]


The disorder is passed on in an  X-linked recessive  fashion. [ 7 ]


Detection usually begins with a routine doctor visit when the  fundal height  is being measured or during an ultrasound examination. When large for gestational age fetuses (LGA) are identified, there are two common causes: maternal diabetes or incorrect dates. However, if these two causes can be ruled out, an ultrasound is performed to detect for overgrowth and other abnormalities. At this point, it becomes essential for a clinical geneticist to assist in the correct selection of tests and possible diagnosis. [ 8 ]


First signs of SGBS may be observed as early as 16 weeks of gestation. Aids to diagnosing might include the presence of macrosomia,  polyhydramnios , elevated maternal serum-α-fetoprotein,  cystic hygroma ,  hydrops fetalis , increased nuchal translucency, craniofacial abnormalities,  visceromegaly , renal abnormalities,  congenital diaphragmatic hernia , polydactyly, and a single umbilical artery. [ 5 ]


If there is a known mutation in the family, prenatal testing is available. Prenatal testing is also possible by looking for evidence of SGBS phenotype in the mother and the positive SGBS phenotype in male family members. Family members who have SGBS may undergo mutational analysis of genes  GPC3 ,  GPC4 , and  CXORF5 . Genomic balance in Xp22 and Xq26 may also be analyzed through array comparative genomic hybridization. Evaluation by a medical geneticist is recommended for those strong indications or likelihood of SGBS and for immediate relatives of those genetically confirmed to have SGBS. [ 5 ]


Due to the high percentage of male deaths during the neonatal period, early detection of tumors is crucial. In order to detect the presence of tumors, screening in SGBS patients should include abdominal ultrasound, urinalysis, and biochemical markers that screen for embryonic tumors. [ 8 ]


PET scan with CT is recommended for accurate diagnostic procedure in adult SGBS patients who have manifested tumors and or cysts, especially those of the kidneys, lungs, and or patients which express atypical lesion of the liver or who may be suspect for neuroblastoma. [ citation needed ]


Once the infant is born, possibility of hypoglycemia must be assessed along with cardiac, genitalia, liver, and adrenal evaluations. Such tests include chest radiographs, electrocardiogram, echocardiogram, renal sonography, and abdominal sonography and CT to test for possible abnormalities. [ 9 ]


Since the syndrome is caused by a genetic mutation in the individual's DNA, a cure is not available. Treatment of the symptoms and management of the syndrome, however, is possible. [ citation needed ]


Due to the likelihood of patients developing tumors, full body CT scans are a recommended diagnostic tool. As there have been cases in which the genetic mutation is accompanied by further genetic presence of the bard 1 gene and presence of triple negative cancers, those with such dual expressions cannot rely upon standardized biopy for determination of cancer, but should resort to further diagnostic tools (i.e. those such as pet scans which measure chemical and decay rate factors for diagnosis). [ citation needed ]


Depending on the manifestation, surgery, special dietary consideration in the event of gastrointestinal affectations, special education, occupational therapy, speech therapy, and physical therapy are some methods of managing the syndrome and associated symptoms. [ 10 ]


SGBS is similar to another overgrowth syndrome called  Beckwith–Wiedemann syndrome . [ citation needed ]


SGBS Cells are a unique tool to study the function of  Human adipocyte biology . These cells are similar to human primary preadipocytes, and may or may not become a popular model instead of Mouse 3T3-L1 cells to study the secretion and adipokine profile in the future. This cellular tool has been described and developed by Dr. Martin Wabitsch, University of Ulm, Germany. [ 11 ]


Sirenomelia , also called  mermaid syndrome , is a rare  congenital deformity  in which the legs are fused together, giving the appearance of a  mermaid 's tail, hence the nickname.


Sirenomelia is classified by the skeletal structure of the lower limb, ranging from class I, where all bones are present and only the soft tissues are fused, to class VII where the only bone present is a fused  femur . [ 1 ]


It has also been classified as an expanded part of the  VACTERL association  and as a form of  caudal regression syndrome . [ 1 ] [ 2 ] [ 3 ]


Sirenomelia is mainly characterized by the fusion of both legs with rotation of the  fibula . It may include the absence of the lower spine, as well as abnormalities of the pelvis and renal organs.  It was previously thought to be a severe form of sacral agensis/caudal regression syndrome, but more recent research confirms that these two conditions are not related. [ 4 ]  In general, the more severe cases of limb fusion correlate with more severe dysplasia in the pelvis. Rather than the two iliac arteries present in fetuses with complete renal agenesis, fetuses with sirenomelia display no branching of the  abdominal aorta , which is always absent. [ 1 ]


Associated defects recorded in cases of sirenomelia include  neural tube defects  ( rachischisis ,  anencephaly , and  spina bifida ),  holoprosencephaly ,  hypoplastic left heart syndrome , other heart defects,  esophageal atresia ,  omphalocele ,  intestinal malrotation ,  persistent cloaca , and other limb defects (most commonly absence of the radius). [ 1 ]


The ultimate cause of sirenomelia is a subject of debate. The first hypothesis of its origin was developed in 1927 and proposed that a lack of blood supply to the lower limbs during their development is responsible for the defect. This "vascular steal" hypothesis was developed in response to the observed absence or severe underdevelopment of the aorta below the umbilical artery, which "steals" the blood supply from the lower limbs. Other hypotheses involve an insult to the embryo between 28 and 32 days affecting the  caudal mesoderm , a  teratogen  exposure affecting the neural tube during  neurulation , and a defect in the twinning process that either stops the process of caudal differentiation or generates a second  primitive streak . [ 1 ]


Maternal  diabetes mellitus  has been associated with  caudal regression syndrome  and sirenomelia, [ 5 ] [ 6 ]  although a few sources question this association. [ 7 ]  Prenatal  cocaine  exposure has also been suggested as an association with sirenomelia. [ 1 ]


In animal models, several genes have been found to cause or be associated with sirenomelia. The  srn  ( siren ) gene is observed to cause hindlimb fusion in homozygous mice. [ 1 ] [ 8 ]  Mice with knockouts or mutations in both  tsg1  and  bmp7  will also have hindlimb fusion. [ 1 ] [ 9 ] [ 10 ]


Though obvious at birth, sirenomelia can be diagnosed as early as 14 weeks gestation on  prenatal ultrasound . When there is low amniotic fluid around the fetus ( oligohydramnios ), the diagnosis is more difficult. [ 1 ]


Sirenomelia is usually fatal. Many pregnancies with a sirenomelic fetus spontaneously  miscarry . One-third to one-half of infants are  stillborn , with all but a few dying in the  neonatal period . [ 1 ]


In cases of  monoamniotic twins  where one is affected, the twin with sirenomelia is protected from  Potter sequence  (particularly  pulmonary hypoplasia  and abnormal facies) by the normal twin's production of amniotic fluid. [ 11 ] [ 1 ]


This condition is found in approximately one out of every 100,000 live births; studies produce rates from 1 in 68,741 to 1 in 97,807. [ 1 ] [ 12 ]  It is 100 to 150 times more likely in identical (monozygotic) twins than in singletons or fraternal twins. [ 11 ] [ 1 ]  Sirenomelia is not associated with any ethnic background, but fetuses with sirenomelia are more likely to be male. [ 1 ]


The word  sirenomelia  derives from the ancient Greek word  seirēn,  referring to the mythological  Sirens , who were sometimes depicted as mermaids, and  melos , meaning "limb".


Sirenomelia was first reported in 1542. In 1927, Otto Kampmeier discovered the association between sirenomelia and  single umbilical artery . [ 1 ]


Only a few individuals who had some functioning kidney tissues have survived the neonatal period. [ 1 ]


Tiffany Yorks of  Clearwater, Florida  (May 7, 1988 – February 24, 2016) [ 13 ]  underwent successful  surgery  in order to separate her legs before she was a year old. She was the longest-surviving sirenomelia patient to date. She had mobility issues due to her fragile leg bones and compensated by using crutches or a wheelchair. She died on February 24, 2016, at the age of 27. [ citation needed ]


Shiloh Jade Pepin (August 4, 1999 – October 23, 2009) was born in  Kennebunkport, Maine ,  United States  with her lower extremities fused, no  bladder , no  uterus , no  rectum , only 6 inches of  large intestine , no  vagina , only one quarter of a  kidney  and one  ovary . Her parents initially anticipated she could expect only a few months of life. At age 4 months, her natural kidney failed, and she began  dialysis . [ 14 ]  A  kidney transplant  at age 2 lasted a number of years, and in 2007 a second kidney transplant was successful. She attended Consolidated  Elementary School . She remained hopeful about her disease and joked often and lived her life happily, despite her challenges, as seen in her  TLC  documentary in "Extraordinary People: Mermaid Girl". Shiloh and her family were debating surgery because of the risks involved, even though it would improve her quality of life. Many people who have this condition undergo surgery when they are young, but Shiloh was already 8 years old in the documentary and had not undergone surgery.  Shiloh was the only one of the three survivors of sirenomelia without surgery for separation of the conjoined legs. [ 15 ]   She died of  pneumonia  on October 23, 2009, at  Maine Medical Center  in  Portland, Maine , at the age of 10; [ 16 ]  having appeared on the  Oprah Winfrey Show  on September 22, 2009. [ 17 ]  Shiloh gained a following of admirers by documenting her condition on  TV ,  Facebook , and the  Internet .


Milagros Cerrón Arauco (April 27, 2004 – October 24, 2019) was born in  Huancayo ,  Peru . Although most of Milagros' internal organs, including her heart and lungs, were in perfect condition, she was born with serious internal defects, including a deformed left  kidney  and a very small right one located very low in her body. In addition, her  digestive ,  urinary tracts  and  genitals  shared a single tube.
This birth defect occurs during the gastrulation week (week 3) of embryonic development. Gastrulation establishes the three germ layers:  ectoderm , mesoderm and  endoderm . It seems that complications such as defects in the urogenital system as mentioned above can be possibly due to malformations in the intermediate mesoderm.


A four-hour operation to insert silicone bags between her legs to stretch the skin was successfully completed on February 8, 2005. A successful operation to separate her legs to just above the knee took place May 31, 2005, in a "Solidarity Hospital" in the district of  Surquillo  in  Lima . The procedure, however, was so intensive that she became  traumatized  to the degree of losing her ability to form proper speech patterns, leaving her nearly  mute . It is not known if this was a  physiological  or  psychological  condition. However, at Milagros' second birthday, her mother reported that she knew more than 50 words. A second operation to complete the separation up to the groin took place on September 7, 2006. [ 18 ]


Her doctor Luis Rubio said he was pleased with the progress Milagros had made, but cautioned that she still needed 10 to 15 years of rehabilitation and more operations before she could lead a normal life, particularly reconstructive surgery to rebuild her rudimentary  anus ,  urethra  and genitalia.


Milagros' parents are from a poor village in Peru's  Andes Mountains ; the Solidarity Hospital had given a job to her father Ricardo Cerrón so that the family could remain in  Lima , while the City of Lima pledged to pay for many of the operations. [ 19 ]


She died on October 24, 2019, at the age of 15. [ 20 ] [ 21 ]


Situs ambiguus  (from  Latin  'ambiguous site'), or  heterotaxy , is a rare  congenital defect  in which the major visceral  organs  are distributed abnormally within the  chest  and  abdomen . Clinically, heterotaxy spectrum generally refers to any defect of  left-right asymmetry  and arrangement of the visceral organs; however, classical heterotaxy requires multiple organs to be affected. This does not include the congenital defect  situs inversus , [ 1 ]  which results when arrangement of all the organs in the abdomen and chest are mirrored, so the positions are opposite the normal placement. Situs inversus is the mirror image of  situs solitus , which is normal asymmetric distribution of the abdominothoracic visceral organs. Situs ambiguus can also be subdivided into left-isomerism and right isomerism based on the defects observed in the  spleen ,  lungs  and  atria  of the  heart .


Individuals with situs inversus or situs solitus do not experience fatal dysfunction of their organ systems, as general  anatomy  and  morphology  of the abdominothoracic organ-vessel systems are conserved. Due to abnormal arrangement of organs in situs ambiguus, orientation across the left-right axis of the body is disrupted early in fetal development, resulting in severely flawed cardiac development and function in 50–80% of cases. They also experience complications with  systemic  and  pulmonary   blood vessels , significant  morbidity , and sometimes  death . [ 2 ]  All  patients  with situs ambiguus lack lateralization and  symmetry  of organs in the  abdominal  and  thoracic  cavities and are  clinically  considered to have a form of heterotaxy syndrome.


Heterotaxy syndrome with  atrial   isomerism  occurs in 1 out of every 10,000 live births and is associated with approximately 3% of  congenital heart disease  cases. [ 3 ]  Additional estimation of incidence and prevalence of isomerism proves difficult due to failure to  diagnose  and underestimation of the disease by clinicians. Furthermore,  right isomerism  is much more easily recognized than left isomerism, contributing to the failure to diagnose. [ 4 ]


Situs ambiguus is a growing field of research with findings dating back to 1973. [ 5 ]


There are a variety of clinical manifestations of situs ambiguus.  Acute  symptoms can be due to both  cardiac  and non-cardiac defects.  Cyanosis  or blue skin coloration, primarily affecting the lips and fingernails, can indicate a systemic or  circulatory  issue. Poor feeding,  failure to thrive , and rapid  shallow breathing  may also be observed due to poor circulation. Upon examination,  arrhythmia  and  heart murmur  may raise further suspicion of a cardiac abnormality. Non-cardiac symptoms include impairments of the  liver  and  gastrointestinal tract .  Biliary atresia , or  inflammation  and destruction of the  bile ducts , may lead to  jaundice .  Vomiting  and swelling of the  abdominal  region are features that suggest improper positioning of the  intestines . Poor positioning of the intestine also makes it more prone to blockage, which can result in numerous  chronic  health issues. [ 4 ]   Asplenia  and  polysplenia  are also possible features of heterotaxy syndrome. [ 6 ]


Due to abnormal cardiac development, patients with situs ambiguus usually develop  right atrial isomerism  consisting of two  bilaterally  paired right atria, or left atrial isomerism consisting of two bilaterally paired left atria. Clinical features and symptoms can vary dependent upon assignment of left versus right atrial isomerism. In either instance, the apex of the heart will be poorly positioned, which should alert a clinician of the likelihood of atrial isomerism. It is estimated that 5–10% of isomeric patients have mesocardia, in which the heart is positioned at the center of the  thorax , 25–50% have  dextrocardia , in which the apex of the heart is pointed toward the right side of the thorax, and 50–70% have  levocardia , in which the apex of the heart is pointed toward the left side of the thorax. [ 2 ]


Right atrial appendage isomerism, also called right atrial isomerism, is a  cardiac  development defect in which the heart has bilateral right atria and  atrial attachments  in the muscle wall, as opposed to the normal right atrium and left atrium. In right atrial isomerism, the  pulmonary   blood oxygen  tract is damaged due to right-left  shunting  of blood. In addition, the  atrial septum  which distinguishes the 2 atria is absent. These impairments, in addition to congestion in the pulmonary tract, allows deoxygenated blood to mix with oxygenated blood, contributing to  cyanosis  and possible  respiratory distress . Poor  systemic circulation  also results due to improper positioning of the  aorta . [ 2 ]


Left atrial appendage isomerism, also called left atrial isomerism, is a cardiac development defect in which the heart has two bilateral left atria and  atrial appendages  in the muscle wall. Left atrial isomerism can have varied clinical manifestations, including a later onset of symptoms.  Heart failure  is often a concern because the  inferior vena cava  is disrupted due to the inappropriate morphology of the  left ventricle  to support the vena cava. [ 2 ]


Abnormal development of the heart results in impaired doubles of conductive nodes, as well as faulty electrical fibers throughout the ventricles. Individuals with right atrial isomerism develop two  sinoatrial nodes , as they have 2 mirrored right atria, whereas those with left atrial isomerism fail to develop a sinus node at all. Thus, patients with left atrial isomerism are more likely to experience  atrial fibrillation , or irregular rapid heart beat, and abnormal heart rhythm, known as  atrial flutter . Development of the  atrioventricular node  and  bundle of His  largely depends on physiological looping of the ventricles. Abnormal looping of the ventricles contributes to  arrhythmia  and  heart block  in fetuses. [ 2 ]


Isomerism of the  bronchial tree  is not typically damaging and presents no significant clinical complications. [ 7 ]   Pulmonary valve stenosis  results in issues of blood flow to the lungs.


Abdominal organs , including the  liver ,  stomach ,  intestinal tract , and  spleen  may be randomly arranged throughout the  left-right axis  of the body. Distribution of these organs largely dictates treatment, clinical outcomes, and further evaluation. [ citation needed ]


The  liver  is typically symmetrical across the left-right axis in patients with situs ambiguus, which is abnormal. A majority of left atrial isomeric patients have defects throughout the  biliary tree , which is responsible for  bile  production, even when the  gall bladder  is functional and morphologically normal. This biliary atresia can lead to  acute  problems such as nutrient  malabsorption , pale stools, dark urine, and abdominal swelling. If this condition continues without proper treatment,  cirrhosis  and  liver failure  become a major concern. Biliary atresia is not usually observed in patients with right atrial isomerism. [ 2 ]


Random positioning of the  stomach  is often one of the first signals of situs ambiguus upon  examination .  Malrotation  of the entire intestinal tract, or improper folding and bulging of the stomach and intestines, results in  bowel obstruction . This impairment leads to vomiting,  abdominal distension ,  mucus  and blood in the stool. Patients may also experience abdominal pain. Intestinal malrotation is more commonly identified in patients with right atrial isomerism than in those with left atrial isomerism. [ citation needed ]


Isomeric patients often experience disruptions to splenic development during  embryogenesis , resulting in an overall lack a spleen ( asplenia ) or development of many spleens ( polysplenia ). Asplenia is most often observed in patients with right atrial isomerism. Polysplenia results in 90% of patients with left atrial isomerism. Although they have many spleens, each is usually ineffective resulting in  functional asplenia . Rarely, left atrial isomeric patients have a single, normal, functional spleen. Patients lacking a functional spleen are in danger of  sepsis  and must be monitored. [ 2 ]


Situs ambiguus has been linked to family history of malformations [ 8 ] [ 9 ]   and maternal  cocaine  use, [ 10 ]  suggesting both genetic and environmental factors play a role. [ 11 ]  Several genes in the  TGF-beta pathway , which controls left-right patterning of visceral organs across the body axis, have been indicated in sporadic and familial cases of atrial isomerism. There is also overlap between genes associated with situs ambiguus and  primary ciliary dyskinesia , likely due to the important role of cilia in establishing  left-right asymmetry . [ 12 ]  The  planar cell polarity  has an important role in positioning these cilia, and thus genes within this pathway are increasingly associated with situs ambiguus. [ 13 ]


Disrupted mitochondria function has also been recently linked to heterotaxy. [ 14 ]


Several genes have been identified in normal development of the right-left axis. [ 15 ]  These genes have been extensively researched. Gene mutations that lead to atrial isomerism is a growing area of research. Mutations in genes that encode proteins in the  TGF-beta pathway , including  NODAL ,  NKX2-5 , and  ZIC3 , have been linked to  tetralogy of Fallot  and  hypoplastic left heart syndrome . [ 16 ] [ 17 ]  Mutations in the  ZIC3  gene, which encodes a  zinc finger  family transcription factor, is linked to a 50% risk of atrial isomerism in families. It is also an  X-linked disorder , so testing for ZIC3 mutations is highly encouraged in male births. [ 18 ]


The most prevalent and best characterized genetic associations of heterotaxy include: [ 2 ]


Pathophysiology in the bronchial tree can be observed by radiography. Under normal development, the bronchial tree consists of two main bronchi that are anatomically different: [ citation needed ]


In situs ambiguus, there is a duplication of either the hyparterial or eparterial bronchus. These features are not associated with any significant clinical complications. [ 19 ]  Mechanisms leading to bronchial duplication are not thoroughly understood.


In  pulmonary valve stenosis , there is a reduction in blood flow to the  lungs  due to an obstruction of the heart at the  pulmonic valve . This contributes to  cyanosis  and  pulmonary hypertension . [ 20 ]


For proper diagnosis of situs ambiguus, cardiac and non-cardiac features must be evaluated. Diagnostic criteria for atrial isomerism includes observation of symmetry of thoracic visceral organs upon echocardiogram, arrhythmia upon electrocardiogram, and chest x-ray for confirmation of the heart's location across the left-right axis. Additional radiographic and cross-sectional imaging may be obtained to evaluate both cardiac and non-cardiac manifestations of situs ambiguus. In addition, a series of gastrointestinal tests can be conducted for observation of intestinal malrotation, as well as a scan of the liver and spleen for biliary function. [ 2 ]


Each of the symptoms of situs ambiguus must be managed with appropriate treatment dependent upon the  organ system  involved. Intestinal malrotation is treated surgically using the  Ladd procedure . This procedure widens a fold in the  peritoneum  so that the intestines can be placed in non-rotated formation. It is not possible to return the bowel to a normal morphology [ 21 ]  However, 89% of patients that undergo the Ladd surgery experience a complete resolution of symptoms. [ citation needed ]


Following cholangiogram, a  Kasai procedure  is usually performed in cases of biliary atresia. In this surgery, a Y-shaped shunt is used to passage bile from the liver directly to the intestine. If this is unsuccessful,  liver transplantation  can be considered based on the overall health of the patient. The Kasai procedure is successful in approximately 80% of patients. [ 22 ]  Following the operation, patients are advised to take fat-soluble vitamins,  choleretics , and  anti-inflammatory medications . [ citation needed ]


Functionally asplenic  patients have an elevated lifetime risk of sepsis, as they have no functional spleen for fighting  infection . For this reason, asplenic patients are under constant observation for any signs of  fever  or infection. In the case of infection, patients are placed on controlled  empiric antibiotic therapy  to avoid development of  antibiotic resistance . [ 23 ]  This therapy battles infection by both  gram-positive  and  gram-negative  bacteria. [ citation needed ]


Right-atrial and left-atrial isomerism and associated pulmonary issues are treated in a series of steps based on the severity of symptoms. Isomeric patients are first treated by inserting a shunt that will move incoming blood through the pulmonary circuit. The  Fontan procedure  routes blood through the patient's single  ventricle , to the  lungs , and into  systemic circulation . This process is favorable in patients aged 2 to 5 years old. About 20–30% of patients will require a heart transplant. [ 24 ]  Left-atrial isomeric patients have less severe complications, as they typically have 2 functional ventricles. In this case, they can undergo biventricular repair to form 2 separate ventricles and functional associated  valves . [ citation needed ]


Prognosis  for patients with situs ambiguus is quite varied, owed to the spectrum of clinical manifestations. [ 25 ]  Infants who experience severe cyanosis at birth may die within hours of delivery if medical intervention is not immediate. Alternatively, longevity of neonates with mild cardiac lesions is unaffected. [ 26 ]  Ten percent of patients born with right atrial isomerism die by the age of 5 without intervention. Improvements in therapies has increased the 5-year survival to 30–74% for right atrial isomeric patients and 65–84% for left atrial isomeric patients based on the cause of their disease. [ citation needed ]


There have been vast amounts of research on the clinical features, racial disparities, and physiological mechanisms of heterotaxy syndrome dating back to 1973. [ citation needed ]


Mishra et al. published a review in November 2015 describing current knowledge of cardiac and non-cardiac abnormalities associated with situs ambiguus. The author stresses the importance of genetic testing prior to deciding a prognosis for affected patients. [ 27 ]  She also proposes prenatal screening and evaluation in cases at risk for development of situs ambiguus. [ citation needed ]