A Congenital Disorder

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A congenital disorder, or congenital disease, is a condition existing at birth and often before birth, or that develops during the first month of life (neonatal disease), regardless of causation. Of these diseases, those characterized by structural deformities are termed "congenital anomalies"; that is a different concept (MeSH) which involves defects in or damage to a developing fetus. A congenital disorder may be the result of genetic abnormalities, the intrauterine (uterus) environment, errors of morphogenesis, infection, or a chromosomal abnormality. The outcome of the disorder will depend on complex interactions between the pre-natal deficit and the post-natal environment. [1] Animal studies indicate that the mother's (and possibly the father's) diet, vitamin intake, and glucose levels prior to ovulation and conception have long-term effects on fetal growth and adolescent and adult disease. [2] Congenital disorders vary widely in causation and abnormalities. Any substance that causes birth defects is known as a teratogen. The older term congenital [3] disorder does not necessarily refer to a genetic disorder despite the similarity of the words. Some disorders can be detected before birth through prenatal diagnosis (screening). Classification Much of the language used for describing congenital conditions predates genomic mapping, and structural conditions are often considered separately from other congenital conditions. It is now known that many metabolic conditions may have subtle structural expression, and structural conditions often have genetic links. Still, congenital conditions are often classified in a structural basis, organized when possible by primary organ system affected. Primarily structural Main article: Congenital abnormality Several terms are used to describe congenital abnormalities. (Some of these are also used to describe noncongenital conditions, and more than one term may apply in an individual condition.) A congenital physical anomaly is an abnormality of the structure of a body part. An anomaly may or may not be perceived as a problem condition. Many, if not most, people have one or more minor physical anomalies if examined carefully. Examples of minor anomalies can include curvature of the 5th finger (clinodactyly), a third nipple, tiny indentations of the skin near the ears (preauricular pits), shortness of the 4th metacarpal or metatarsal

Transcript of A Congenital Disorder

Page 1: A Congenital Disorder

A congenital disorder, or congenital disease, is a condition existing at birth and often before birth, or that develops during the first month of life (neonatal disease), regardless of causation. Of these diseases, those characterized by structural deformities are termed "congenital anomalies"; that is a different concept (MeSH) which involves defects in or damage to a developing fetus.

A congenital disorder may be the result of genetic abnormalities, the intrauterine (uterus) environment, errors of morphogenesis, infection, or a chromosomal abnormality. The outcome of the disorder will depend on complex interactions between the pre-natal deficit and the post-natal environment.[1] Animal studies indicate that the mother's (and possibly the father's) diet, vitamin intake, and glucose levels prior to ovulation and conception have long-term effects on fetal growth and adolescent and adult disease.[2] Congenital disorders vary widely in causation and abnormalities. Any substance that causes birth defects is known as a teratogen.

The older term congenital[3] disorder does not necessarily refer to a genetic disorder despite the similarity of the words. Some disorders can be detected before birth through prenatal diagnosis (screening).

Classification

Much of the language used for describing congenital conditions predates genomic mapping, and structural conditions are often considered separately from other congenital conditions. It is now known that many metabolic conditions may have subtle structural expression, and structural conditions often have genetic links. Still, congenital conditions are often classified in a structural basis, organized when possible by primary organ system affected.

Primarily structural

Main article: Congenital abnormality

Several terms are used to describe congenital abnormalities. (Some of these are also used to describe noncongenital conditions, and more than one term may apply in an individual condition.)

A congenital physical anomaly is an abnormality of the structure of a body part. An anomaly may or may not be perceived as a problem condition. Many, if not most, people have one or more minor physical anomalies if examined carefully. Examples of minor anomalies can include curvature of the 5th finger (clinodactyly), a third nipple, tiny indentations of the skin near the ears (preauricular pits), shortness of the 4th metacarpal or metatarsal bones, or dimples over the lower spine (sacral dimples). Some minor anomalies may be clues to more significant internal abnormalities.

Birth defect is a widely used term for a congenital malformation, i.e. a congenital, physical anomaly which is recognizable at birth, and which is significant enough to be considered a problem. According to the CDC, most birth defects are believed to be caused by a complex mix of factors including genetics, environment, and behaviors,[1] though many birth defects have no known cause.

A congenital malformation is a congenital physical anomaly that is deleterious, i.e. a structural defect perceived as a problem. A typical combination of malformations affecting more than one body part is referred to as a malformation syndrome.

Some conditions are due to abnormal tissue development: o A malformation is associated with a disorder of tissue development.[4] Malformations

often occur in the first trimester.o A dysplasia is a disorder at the organ level that is due to problems with tissue

development.[4]

It is also possible for conditions to arise after tissue is formed:

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o A deformation is a condition arising from mechanical stress to normal tissue.[4]

Deformations often occur in the second or third semester, and can be due to oligohydramnios.

A disruption involves breakdown of normal tissues.[4]

When multiple effects occur in a specified order, it is known as a sequence. When the order is not known, it is a syndrome.

Other

Genetic disorders or diseases are all congenital, though they may not be expressed or recognized until later in life. Genetic diseases may be divided into single-gene defects, multiple-gene disorders, or chromosomal defects. Single-gene defects may arise from abnormalities of both copies of an autosomal gene (a recessive disorder) or of only one of the two copies (a dominant disorder). Some conditions result from deletions or abnormalities of a few genes located contiguously on a chromosome. Chromosomal disorders involve the loss or duplication of larger portions of a chromosome (or an entire chromosome) containing hundreds of genes. Large chromosomal abnormalities always produce effects on many different body parts and organ systems.

A congenital metabolic disease is also referred to as an inborn error of metabolism. Most of these are single gene defects, usually heritable. Many affect the structure of body parts but some simply affect the function.

Other well defined genetic conditions may affect the production of hormones, receptors, structural proteins, and ion channels.

Causes

Antibiotics

Use of antibiotics around the time of conception, particularly sulfonamides and nitrofurantoin are associated with major birth defects. Whether or not this association is causal has not been determined.[5]

Sulfonamide (medicine)

Sulfonamide or sulphonamide is the basis of several groups of drugs. The original antibacterial sulfonamides (sometimes called sulfa drugs or sulpha drugs) are synthetic antimicrobial agents that contain the sulfonamide group. Some sulfonamides are also devoid of antibacterial activity, e.g., the anticonvulsant sultiame. The sulfonylureas and thiazide diuretics are newer drug groups based on the antibacterial sulfonamides.[1]

Sulfa allergies are common,[2] hence medications containing sulfonamides are prescribed carefully. It is important to make a distinction between sulfa drugs and other sulfur-containing drugs and additives, such as sulfates and sulfites, which are chemically unrelated to the sulfonamide group, and do not cause the same hypersensitivity reactions seen in the sulfonamides.

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Sulfonamide functional group

Hydrochlorothiazide is a sulfonamide and a thiazide.

Furosemide is a sulfonamide, but not a thiazide.

NitrofurantoinNitrofurantoin is an antibiotic which is marketed under the following brand names; Furadantin, Macrobid, Macrodantin, Nitrofur Mac, Nitro Macro, Nifty-SR, Martifur-MR, Martifur-100 (in India), Urantoin, and Uvamin (in Middle East). It is usually used in treating urinary tract infection. Like many other drugs, it is often used against E. coli.

Use

Resistance to other antibiotics has led to increased interest in this agent.[2]

It is sometimes described as being appropriate to use in pregnant patients[3] (along with other agents such as sulfisoxazole or cephalexin).[4] This is in contrast to agents such as trimethoprim and ciprofloxacin which may not be appropriate for pregnant women.

Pharmacology

Organisms are said to be susceptible to nitrofurantoin if their minimum inhibitory concentration (MIC) is 32 μg/mL or less. The peak blood concentration of nitrofurantoin following an oral dose of nitrofurantoin 100 mg, is less than 1 μg/mL and may be undetectable; tissue penetration is negligible; the drug is well concentrated in the urine: 75% of the dose is rapidly metabolised by the liver, but 25% of the dose is excreted in the urine unchanged, reliably achieving levels of 200 μg/ml or more. For this reason, nitrofurantoin cannot be used to treat anything other than simple cystitis.

At the concentrations achieved in urine, nitrofurantoin is bacteriocidal.

Nitrofurantoin and the quinolone antibiotics are mutually antagonistic in vitro. It is not known whether this is of clinical significance, but the combination should be avoided.

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Resistance to nitrofurantoin may be chromosomal or plasmid mediated and involves inhibition of nitrofuran reductase.[5] Acquired resistance in E. coli continues to be rare.

Nitrofurantoin and its metabolites are excreted mainly by the kidneys. In renal impairment, the concentration achieved in urine may be subtherapeutic. Nitrofurantoin should not be used in patients with a creatinine clearance of 60 mL/min or less. However a retrospective chart review may suggest that Nitrofurantoin is not contraindicated in this population.[6]

Mechanism

The mechanism of action of nitrofurantoin is unique and complex. The drug works by damaging bacterial DNA, since its reduced form is highly reactive. This is made possible by the rapid reduction of nitrofurantoin inside the bacterial cell by flavoproteins (nitrofuran reductase) to multiple reactive intermediates that attack ribosomal proteins, DNA,[7] respiration, pyruvate metabolism and other macromolecules within the cell. It is not known which of the actions of nitrofurantoin is primarily responsible for its bactericidal activity.

Uses

The normal adult dose of nitrofurantoin is 50 to 100 mg four times daily for seven days. If a long-acting preparation (e.g., Macrobid) is used then the dose is 100 mg twice daily. The pediatric dose is 5–7 mg/kg/day in four divided doses.[8] or when in 25 mg/5ml oral suspension then pediatric dose is 3 mg/kg/day in four divided doses.[9] Nitrofurantoin should be taken with food, as this improves the absorption of the drug by 45%.

Nitrofurantoin is only clinically proven for use against E. coli or Staph. saprophyticus. It may also have in vitro activity against:

Coagulase-negative staphylococci Enterococcus faecalis, Staphylococcus aureus, Streptococcus agalactiae, Citrobacter species, Klebsiella species,

and is used in the treatment of infections caused by these organisms. Only a minority of Enterobacter species and Klebsiella species are sensitive to nitrofurantoin; nitrofurantoin has no activity against

Acinetobacter species, Morganella species, Proteus species, Providentia species, Serratia species, or Pseudomonas species.

Nitrofurantoin must never be used to treat pyelonephritis,[10] renal abscess, and pyeloempyema because of extremely poor tissue penetration and low blood levels. Urinary catheter infections may be treated with nitrofurantoin if there are no systemic features; the catheter must be changed after 48 hours of antibiotics and treatment is ineffective if the catheter is not replaced or removed.

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Adverse effects

Nitrofurantoin can cause nausea and vomiting, fever, rash, hypersensitivity pneumonitis.[citation needed] It can also cause pulmonary fibrosis.[11] All these side effects are much more common in the elderly.

Patients should be informed that nitrofurantoin colours urine a dark orange-brown; this is completely harmless.

Neonates (babies up to the age of one month) have immature enzyme systems in their red blood cells (glutathione instability) and nitrofurantoin must therefore not be used because it can cause haemolytic anaemia. For the same reason, nitrofurantoin should not be given to pregnant women after 38 weeks of pregnancy, or who are about to give birth.

Nitrofurantoin is contraindicated in patients with decreased renal function (CrCl < 60mL/min) due to systemic accumulation and subtherapeutic levels reached in the urinary tract. However a retrospective chart review may suggest that Nitrofurantoin is not contraindicated in this population.[6]

Use in food

Residues from the breakdown of nitrofuran veterinary antibiotics, including nitrofurantoin, have been found in chicken in Vietnam, China, Brazil, and Thailand.[12] The European Union banned the use of nitrofurans in food producing animals by classifying it in ANNEX IV (list of pharmacologically active substances for which no maximum residue limits can be fixed) of the Council Regulation 2377/90. The Food and Drug Administration (FDA) of the United States has prohibited furaltadone since February 1985 and withdrew the approval for the other nitrofuran drugs (except some topical uses) in January 1992. The topical use of furazolidone and nitrofurazone was prohibited in 2002. Australia prohibited the use of nitrofurans in food production in 1992. Japan did not allocate MRLs for nitrofurans leading to the implementation of a "zero tolerance or no residue standard". In Thailand, the Ministry of Health issued in 2001 Proclamation No. 231 MRL of veterinary drug in food which did not allocate MRL for nitrofurans. The Ministry of Agriculture and Cooperatives had already prohibited importation and use of furazolidone and nitrofurazone in animal feed in 1999 which was extended to all nitrofurans in 2002. Several metabolites of nitrofurans, such as furazolidone, furaltadone and nitrofurazone cause cancer or genetic damage in rats.[12]

Precautions

Nitrofurantoin must be taken with food and can cause bleeding in the stomach, vomiting and other gastrointestinal disruptions if these warnings are not adhered to. Nitrofurantoin is contraindicated in patients with glucose-6-phosphate dehydrogenase deficiency because of risk of extravascular hemolysis resulting in anemia.

Trade names

Furadantin (U.S., UK) Macrobid (long acting preparation for twice daily dosing available in U.S., Canada, and UK) Macrodantin (U.S., UK) Furatin (India) Furanit

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Uvamin (Middle East)

List of congenital disordersFrom Wikipedia, the free encyclopedia

List of congenital disorders

Numerical

5p syndrome - see Cri du chat

A

Aicardi syndrome Albinism Amelia and hemimelia Amniotic Band syndrome Anencephaly Angelman syndrome Aposthia Arnold-Chiari malformation

B

Bannayan-Zonana syndrome Bardet-Biedl syndrome Barth syndrome Basal Cell Nevus syndrome Beckwith-Wiedemann syndrome Benjamin syndrome Bladder exstrophy Bloom syndrome

C

Cat Eye syndrome Sotos syndrome Cerebral Gigantism CHARGE syndrome Chromosome 16 Abnormalities Chromosome 18 Abnormalities Chromosome 20 Abnormalities Chromosome 22 Abnormalities Cleft lip/palate Club foot Congenital adrenal hyperplasia (CAH) Congenital Central Hypoventilation Syndrome

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Congenital Diaphragmatic Hernia (CDH) Congenital insensitivity to pain with anhidrosis (CIPA) Conjoined twins Costello syndrome Craniopagus parasiticus Cri du chat syndrome Cyclopia Cystic fibrosis

D

De Lange syndrome Diphallia Distal Trisomy 10q Down syndrome

E

Ectodermal Dysplasia Ectopia cordis Ectrodactyly Encephalocele

F

Fetal Alcohol Syndrome Fetofetal Transfusion Freeman-Sheldon syndrome

G

Gastroschisis Goldenhar syndrome

H

Harlequin type ichthyosis Heart disorders (Congenital heart defects) Hemifacial Microsomia Holoprosencephaly Huntington's disease Hirschsprung's Disease, or congenital aganglionic megacolon Hypoglossia Hypomelanism or hypomelanosis (albinism) Hypospadias

I

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Imperforate anus Incontinentia pigmenti Intestinal neuronal dysplasia Ivemark syndrome

J

Jacobsen syndrome

K

Klinefelter syndrome Kabuki syndrome

L

Larsen syndrome Laurence-Moon syndrome Lissencephaly

M

Microcephaly Microtia Monosomy 9p- Myelokathexis

N

Nager's Syndrome Nail-Patella syndrome Neonatal Jaundice Neurofibromatosis Neuronal Ceroid-Lipofuscinosis Noonan syndrome

O

Ochoa syndrome Oculocerebrorenal syndrome

P

Pallister-Killian syndrome Pectus Excavatum Pierre Robin syndrome Polydactyly

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Prader-Willi syndrome Proteus syndrome Prune belly syndrome

R

Radial aplasia Rett syndrome Robinow syndrome Rubinstein-Taybi syndrome

S

Schizencephaly Sirenomelia Situs inversus Smith-Lemli-Opitz syndrome Smith-Magenis syndrome Spina bifida Strabismus Sturge-Weber syndrome Syphilis, Congenital

T

Teratoma Treacher Collins syndrome Trichothiodystrophy Triple-X Females Trisomy 13 Trisomy 9 Turner syndrome

U

Umbilical hernia Usher syndrome

W

Waardenburg's syndrome Werner syndrome Wolf-Hirschhorn syndrome

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Aicardi syndromeFrom Wikipedia, the free encyclopedia

Aicardi syndrome

Classification and external resources

ICD-10 G 93.8.

ICD-9 742.2

OMIM 304050

DiseasesDB 29761

MedlinePlus 001664

eMedicine ped/58

Aicardi syndrome is a rare genetic malformation syndrome characterized by the partial or complete absence of a key structure in the brain called the corpus callosum, the presence of retinal abnormalities, and seizures in the form of infantile spasms. Aicardi syndrome is theorized to be caused by a defect on the X chromosome as it has thus far only been observed in girls or in boys with Klinefelter's syndrome. Confirmation of this theory awaits the discovery of the gene which causes Aicardi syndrome. Symptoms typically appear before a baby reaches about 5 months of age.[citation needed]

Contents

1 History 2 Epidemiology 3 Genetics 4 Features 5 Diagnosis 6 Treatment 7 Prognosis 8 References 9 External links

History

This disorder was first recognized as a distinct syndrome in 1965 by Jean Aicardi, a French neurologist. A review article by Dr. Aicardi (Aicardi J, Aicardi syndrome: old and new findings, Int Pediatr. 1998;14(1):5-8) describes the syndrome. Aicardi syndrome should not be confused with Aicardi-Goutières syndrome, a distinct disorder.[citation needed]

Epidemiology

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Worldwide prevalence of Aicardi Syndrome is estimated at several thousand, with approximately 900 cases reported in the United States.[1]

Genetics

Almost all reported cases of Aicardi syndrome have been in females. The few males that have been identified with Aicardi syndrome have proved to have 47 chromosomes including an XXY sex chromosome complement, a condition called Klinefelter syndrome.[citation needed]

Aicardi syndrome appears to be lethal in normal males who have only one X chromosome (and a Y chromosome). In other words, Aicardi syndrome appears to be inherited in an X-linked dominant pattern due to a mutant gene on the X chromosome that is lethal in XY males.[citation needed]

All cases of Aicardi syndrome are thought to be due to new mutations. No person with Aicardi syndrome is known to have transmitted the X-linked gene responsible for the syndrome to the next generation.

Features

Children are most commonly identified with Aicardi syndrome before the age of five months. A significant number of girls are products of normal births and seem to be developing normally until around the age of three months, when they begin to have infantile spasms. The onset of infantile spasms at this age is due to closure of the final neural synapses in the brain, a stage of normal brain development.[citation

needed]

Diagnosis

Aicardi syndrome is typically characterized by the following triad of features - however, one of the "classic" features being missing does not preclude a diagnosis of Aicardi Syndrome, if other supporting features are present.[2]

1. Partial or complete absence of the corpus callosum in the brain (agenesis of the corpus callosum);2. Eye abnormalities known as "lacunae" of the retina that are quite specific to this disorder; and3. The development in infancy of seizures that are called infantile spasms.

Other types of defects of the brain such as microcephaly, polymicrogyria, porencephalic cysts and enlarged cerebral ventricles due to hydrocephalus are also common in Aicardi syndrome.

Treatment

Treatment of Aicardi syndrome primarily involves management of seizures and early/continuing intervention programs for developmental delays.

Additional complications sometimes seen with Aicardi syndrome include porencephalic cysts and hydrocephalus, and gastro-intestinal problems. Treatment for prencephalic cysts and/or hydrocephalus is often via a shunt or endoscopic fenestration of the cysts, though some require no treatment. Placement of a feeding tube, fundoplication, and surgeries to correct hernias or other gastrointestinal structural problems are sometimes used to treat gastro-intestinal issues.

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Prognosis

The prognosis varies widely from case to case, depending on the severity of the symptoms. However, almost all people reported with Aicardi syndrome to date have experienced developmental delay of a significant degree, typically resulting in moderate to profound mental retardation. The age range of the individuals reported with Aicardi syndrome is from birth to the mid 40s. There is no cure for this syndrome.

Albino deer

An Albino American Alligator

European Mole (Talpa europaea Linnaeus, 1758)

An Albino Kookaburra

Albino rabbit

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An Albino Squirrel, (Colombo, Sri Lanka)

Common and albinotic colour forms of land snail Pseudofusulus varians

An albino individual of freshwater snail Biomphalaria glabrata. All snails in the family Planorbidae have the red oxygen transport pigment haemoglobin, but this is especially apparent in albino animals.

Amelia (birth defect)From Wikipedia, the free encyclopedia

For other uses, see Amelia (disambiguation).

Amelia

Classification and external resources

ICD-10 Q 73.0

ICD-9 755.21, 755.31, 755.4

Amelia (from Greek ἀ- "lack of" plus μέλος (plural: μέλεα or μέλη) "limb") is the birth defect of lacking one or more limbs. It can also result in a shrunken or deformed limb. For example, a child might be born without an elbow or forearm. The term may be modified to indicate the number of legs or arms missing at birth, such as tetra-amelia for the absence of all four limbs. A related term is meromelia, which is the partial absence of a limb or limbs. [1]

Contents

1 Causes 2 Description 3 Symptoms 4 Notes 5 See also

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6 External links

Causes

The complete absence of an arm or leg in amelia occurs as a result of the limb formation process being either prevented or interrupted very early in the developing embryo: between 24 and 36 days following fertilization.[2] Tetra-amelia syndrome appears to have an autosomal recessive pattern of inheritance - that is, the parents of an individual with tetra-amelia syndrome each carry one copy of the mutated gene, but do not show signs and symptoms of the condition.[3] In a few cases, amelia may be attributed to health complications during the early stages of pregnancy, including infection, failed abortion or complications associated with removal of an IUD after pregnancy.

Description

Amelia may be present as an isolated defect, but it is often associated with major malformations in other organ systems. These frequently include cleft lip and/or palate, body wall defects, malformed head, and defects of the neural tube, kidneys, and diaphragm. Facial clefts may be accompanied by other facial anomalies such as abnormally small jaw, and missing ears or nose. The body wall defects allow internal organs to protrude through the abdomen. Head malformations may be minor to severe with a near absence of the brain. The diaphragm may be herniated or absent and one or both kidneys may be small or absent.

Symptoms

The diagnosis of tetra-amelia syndrome is established clinically and can be made on routine prenatal ultrasonography. WNT3 is the only gene known to be associated with tetra-amelia syndrome. Molecular genetic testing on a clinical basis can be used to diagnose the incidence of the syndrome. The mutation detection frequency is unknown as only a limited number of families have been studied. Affected infants are often stillborn or die shortly after birth.[4]

Amniotic band syndromeFrom Wikipedia, the free encyclopedia

Amniotic band syndrome

Amniotic band syndrome (also known as "ADAM complex,"[1] "Amniotic band sequence,"[1] "Congenital constriction bands,"[1] and "Pseudoainhum"[1]) is a congenital disorder caused by entrapment of fetal parts (usually a limb or digits) in fibrous amniotic bands while in utero.

Contents

1 Epidemiology 2 Features 3 Natural history 4 Diagnosis 5 Treatment

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6 Prognosis 7 Prevention 8 See also 9 References 10 External links

Epidemiology

Amniotic banding affects approximately 1 in 1,200 live births. It is also believed to be the cause of 178 in 10,000 miscarriages. Up to 50% of cases have other congenital anomalies including cleft lip, cleft palate, and clubfoot deformity. Hand and finger anomalies occur in up to 80%.

Features

The constriction of appendages by amniotic bands may result in:

1. Constriction rings around the digits, arms and legs2. Swelling of the extremities distal to the point of constriction (congenital lymphedema)3. Amputation of digits, arms and legs (congenital amputation)

A strong relationship between ABS and clubfoot exists. A 31.5% of associated clubfoot deformity and ABS can be correlated with 20% occurring bilaterally. Other abnormalities found with ABS include: clubhands, cleft lip, and/or cleft palate, and hemangioma.

Natural history

To explain the cause of ABS, there are two main theories.

The amniotic band theory is that ABS occurs due to a partial rupture of the amniotic sac. This rupture involves only the amnion; the chorion remains intact. Fibrous bands of the ruptured amnion float in the amniotic fluid and can encircle and trap some part of the fetus. Later, as the fetus grows but the bands do not, the bands become constricting. This constriction reduces blood circulation, hence causes congenital abnormalities. In some cases a complete "natural" amputation of a digit(s) or limb may occur before birth or the digit(s) or limbs may be necrotic (dead) and require surgical amputation following birth.

The vascular disruption theory: Because the constricting mechanism of the amniotic band theory does not explain the high incidence of cleft palate and other forms of cleft defects occurring together with ABS, this co-occurrence suggests an "intrinsic" defect of the blood circulation.

Diagnosis

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Amniotic band syndrome is often difficult to detect before birth as the individual strands are small and hard to see on ultrasound. Often the bands are detected indirectly because of the constrictions and swelling upon limbs, digits, etc. Misdiagnosis is also common, so if there are any signs of amniotic bands, further detailed ultrasound tests should be done to assess the severity. 3D ultrasound and MRI can be used for more detailed and accurate diagnosis of bands and the resulting damage/danger to the fetus.

Treatment

Treatment usually occurs after birth and where plastic and reconstructive surgery is considered to treat the resulting deformity.[2] Plastic surgery ranges from simple to complex depending on the extent of the deformity. Physical and occupational therapy may be needed long term.

In rare cases, if diagnosed in utero, fetal surgery may be considered to save a limb which is in danger of amputation or other deformity. This typically would not be attempted if neither vital organs nor the umbilical cord are affected. This operation has been able to be successfully performed on foetuses as young as 22 weeks.[3] The surgery took place at Melbourne's Monash Medical Centre in Australia and is believed to be the earliest surgery of its type, as surgeons usually hold off on operating until a mother is at least 28 weeks gestation.[4] There are also several facilities in the United States that have performed successful amniotic band release surgery.

[edit] Prognosis

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

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

The number of cases of miscarriage that can be contributed to ABS is unknown, although it has been reported that it may be the cause of 178 in 10,000 miscarriages.

[edit] Prevention

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

AnencephalyFrom Wikipedia, the free encyclopedia

Anencephaly

Classification and external resources

A front view of an anencephalic fetus

ICD-10 Q 00.0

ICD-9 740.0

OMIM 206500

DiseasesDB 705

eMedicine neuro/639

MeSH C10.500.680.196

Anencephaly is a cephalic disorder that results from a neural tube defect that occurs when the cephalic (head) end of the neural tube fails to close, usually between the 23rd and 26th day of pregnancy, resulting in the absence of a major portion of the brain, skull, and scalp.[1] Children with this disorder are born without a forebrain, the largest part of the brain consisting mainly of the cerebral hemispheres (which include the neocortex, which is responsible for higher-level cognition, i.e., thinking). The remaining brain tissue is often exposed—not covered by bone or skin.[2] Most babies with this genetic disorder do not survive birth.

Contents

1 Signs and symptoms 2 Causes

o 2.1 Relation to genetic ciliopathy 3 Diagnosis

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4 Prognosis 5 Epidemiology 6 See also 7 References 8 External links

Signs and symptoms

An anencephalic newborn

The National Institute of Neurological Disorders and Stroke (NINDS) describes the presentation of this condition as follows: "A baby born with anencephaly is usually blind, deaf, unconscious, and unable to feel pain. Although some individuals with anencephaly may be born with a main brain stem, the lack of a functioning cerebrum permanently rules out the possibility of ever gaining consciousness. Reflex actions such as breathing and responses to sound or touch occur."[2]

Causes

The cause of anencephaly is disputed. Generally, neural tube defects do not follow direct patterns of heredity, though there is some indirect evidence of inheritance, [3] and recent animal models indicate a possible association with deficiencies of the transcription factor TEAD2.[4] Studies show that a woman who has had one child with a neural tube defect such as anencephaly has about a 3% risk of having another child with a neural tube defect.[citation needed]

It is known that women taking certain medications for epilepsy and women with insulin-dependent diabetes have a higher risk of having a child with a neural tube defect.[citation needed] Genetic counseling is usually offered to women at a higher risk of having a child with a neural tube defect to discuss available testing.

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Recent studies have shown that the addition of folic acid to the diet of women of child-bearing age may significantly reduce, although not eliminate, the incidence of neural tube defects. Therefore, it is recommended that all women of child-bearing age consume 0.4 mg of folic acid daily,[2] especially those attempting to conceive or who may possibly conceive, as this can reduce the risk to 0.03%.[citation needed] It is not advisable to wait until pregnancy has begun, since by the time a woman knows she is pregnant, the critical time for the formation of a neural tube defect has usually already passed. A physician may prescribe even higher dosages of folic acid(4 mg/day) for women who have had a previous pregnancy with a neural tube defect.[original research?]

Anencephaly and other physical and mental deformities have also been blamed on a high exposure to such toxins as lead, chromium, mercury, and nickel.[5]

Relation to genetic ciliopathy

Until recently, medical literature did not indicate a connection among many genetic disorders, both genetic syndromes and genetic diseases, that are now being found to be related. As a result of new genetic research, some of these are, in fact, highly related in their root cause despite the widely varying set of medical symptoms that are clinically visible in the disorders. Anencephaly is one such disease, part of an emerging class of diseases called ciliopathies. The underlying cause may be a dysfunctional molecular mechanism in the primary cilia structures of the cell, organelles which are present in many cellular types throughout the human body. The cilia defects adversely affect "numerous critical developmental signaling pathways" essential to cellular development and thus offer a plausible hypothesis for the often multi-symptom nature of a large set of syndromes and diseases. Known ciliopathies include primary ciliary dyskinesia, Bardet-Biedl syndrome, polycystic kidney and liver disease, nephronophthisis, Alstrom syndrome, Meckel-Gruber syndrome, and some forms of retinal degeneration.[6]

Diagnosis

Ultrasound image of fetus with anencephaly

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Anencephaly can often be diagnosed before birth through an ultrasound examination. The maternal serum alpha-fetoprotein (AFP screening)[7] and detailed fetal ultrasound[8] can be useful for screening for neural tube defects such as spina bifida or anencephaly.

Prognosis

This section does not cite any references or sources. Please help improve this section by adding citations to reliable sources. Unsourced material may be challenged and removed. (June 2011)

There is no cure or standard treatment for anencephaly and the prognosis for patients is death. Most anencephalic fetuses do not survive birth, accounting for 55% of non-aborted cases. If the infant is not stillborn, then he or she will usually die within a few hours or days after birth from cardiorespiratory arrest.

In almost all cases, anencephalic infants are not aggressively resuscitated because there is no chance of the infant ever achieving a conscious existence. Instead, the usual clinical practice is to offer hydration, nutrition, and comfort measures and to "let nature take its course". Artificial ventilation, surgery (to fix any co-existing congenital defects), and drug therapy (such as antibiotics) are usually regarded as futile efforts. Clinicians and medical ethicists may view the provision of nutrition and hydration as medically futile.

Epidemiology

In the United States, approximately 1 out of 150,000 to 200,000 babies is born with anencephaly each year. Research has suggested that, overall, female babies are more likely to be affected by the disorder.[9]

Angelman syndromeFrom Wikipedia, the free encyclopedia

Angelman syndrome

Classification and external resources

ICD-10 Q 93.5

ICD-9 759.89

OMIM 105830

DiseasesDB 712

MeSH D017204

Angelman syndrome (AS) is a neuro-genetic disorder characterized by intellectual and developmental delay, sleep disturbance, seizures, jerky movements (especially hand-flapping), frequent laughter or smiling, and usually a happy demeanor.

Page 21: A Congenital Disorder

AS is a classic example of genomic imprinting in that it is usually caused by deletion or inactivation of genes on the maternally inherited chromosome 15 while the paternal copy, which may be of normal sequence, is imprinted and therefore silenced. The sister syndrome, Prader-Willi syndrome, is caused by a similar loss of paternally inherited genes and maternal imprinting. AS is named after a British pediatrician, Dr. Harry Angelman, who first described the syndrome in 1965.[1] An older, alternative term for AS, happy puppet syndrome, is generally considered pejorative and stigmatizing so it is no longer the accepted term, though it is sometimes still used as an informal term of diagnosis. People with AS are sometimes known as "angels", both because of the syndrome's name and because of their youthful, happy appearance.

Contents

1 History 2 Prevalence 3 Pathophysiology 4 Clinical features 5 Neurophysiology 6 Diagnosis 7 Treatment and care 8 Prognosis 9 See also 10 References 11 External links

History

"Boy with a Puppet" or "A child with a drawing" by Giovanni Francesco Caroto.

Page 22: A Congenital Disorder

Dr. Harry Angelman, a pediatrician working in Warrington, England, first reported three children with this condition in 1965.[1] Angelman later described his choice of the title "Puppet Children" to describe these cases as being related to an oil painting he had seen while vacationing in Italy:

The history of medicine is full of interesting stories about the discovery of illnesses. The saga of Angelman's syndrome is one such story. It was purely by chance that nearly thirty years ago (e.g., circa 1964) three handicapped children were admitted at various times to my children's ward in England. They had a variety of disabilities and although at first sight they seemed to be suffering from different conditions I felt that there was a common cause for their illness. The diagnosis was purely a clinical one because in spite of technical investigations which today are more refined I was unable to establish scientific proof that the three children all had the same handicap. In view of this I hesitated to write about them in the medical journals. However, when on holiday in Italy I happened to see an oil painting in the Castelvecchio Museum in Verona called . . . a Boy with a Puppet. The boy's laughing face and the fact that my patients exhibited jerky movements gave me the idea of writing an article about the three children with a title of Puppet Children. It was not a name that pleased all parents but it served as a means of combining the three little patients into a single group. Later the name was changed to Angelman syndrome. This article was published in 1965 and after some initial interest lay almost forgotten until the early eighties.

—Angelman quoted by Charles Williams[2]

Case reports from the United States first began appearing in the medical literature in the early 1980s. [3][4]

In 1987, it was first noted that around half of the children with AS have a small piece of chromosome 15 missing (chromosome 15q partial deletion).[5]

Prevalence

Though the prevalence of Angelman syndrome is not precisely known, there are some estimates. The best data available are from studies of school age children, ages 6–13 years, living in Sweden and from Denmark where the diagnosis of AS children in medical clinics was compared to an 8 year period of about 45,000 births. The Swedish study showed an AS prevalence of about 1/20,000[6] and the Danish study showed a minimum AS prevalence of about 1/10,000.[7]

Pathophysiology

Page 23: A Congenital Disorder

Chromosome 15

Angelman syndrome is caused by the loss of the normal maternal contribution to a region of chromosome 15, most commonly by deletion of a segment of that chromosome. Other causes include uniparental disomy, translocation, or single gene mutation in that region. A healthy person receives two copies of chromosome 15, one from the mother, the other from the father. However, in the region of the chromosome that is critical for Angelman syndrome, the maternal and paternal contribution express certain genes very differently. This is due to gender-related epigenetic imprinting; the biochemical mechanism is DNA methylation. In a normal individual, the maternal allele is expressed and the paternal allele is silenced. If the maternal contribution is lost or mutated, the result is Angelman syndrome. (When the paternal contribution is lost, by similar mechanisms, the result is Prader-Willi syndrome.) It should be noted that the methylation test that is performed for Angelman syndrome (a defect in UBE3A) is actually looking for the gene's neighbour SNRPN (which has the opposite pattern of methylation).[8]

Angelman syndrome can also be the result of mutation of a single gene. This gene (UBE3A,[9] part of the ubiquitin pathway) is present on both the maternal and paternal chromosomes, but differs in the pattern of methylation (imprinting). The paternal silencing of the UBE3A gene occurs in a brain region-specific manner; in the hippocampus and cerebellum, the maternal allele is almost exclusively the active one. The most common genetic defect leading to Angelman syndrome is an ~4Mb (mega base) maternal deletion in chromosomal region 15q11-13 causing an absence of UBE3A expression in the paternally imprinted brain

Page 24: A Congenital Disorder

regions. UBE3A codes for an E6-AP ubiquitin ligase, which chooses its substrates very selectively and the four identified E6-AP substrates have shed little light on the possible molecular mechanisms underlying the human Angelman syndrome mental retardation state.

Initial studies of mice that do not express maternal UBE3A show severe impairments in hippocampal memory formation. Most notably, there is a deficit in a learning paradigm that involves hippocampus-dependent contextual fear conditioning. In addition, maintenance of long-term synaptic plasticity in hippocampal area CA1 in vitro is disrupted in Ube3a-/- mice. These results provide links amongst hippocampal synaptic plasticity in vitro, formation of hippocampus-dependent memory in vivo, and the molecular pathology of Angelman syndrome.

Clinical features

The following list features of Angelman syndrome and their relative frequency in affected individuals.[10]

Consistent (100%)

Developmental delay, functionally severe Speech impairment, no or minimal use of words; receptive and non-verbal communication skills higher

than verbal ones Movement or balance disorder, usually ataxia of gait and/or tremulous movement of limbs Behavioral uniqueness: any combination of frequent laughter/smiling; apparent happy demeanor; easily

excitable personality, often with hand flapping movements; hypermotoric behavior; short attention span

Frequent (more than 80%)

Delayed, disproportionate growth in head circumference, usually resulting in microcephaly (absolute or relative) by age 2

Seizures, onset usually < 3 years of age Abnormal EEG, characteristic pattern with large amplitude slow-spike waves

Associated (20 - 80%)

Strabismus Hypopigmented skin and eyes Tongue thrusting; suck/swallowing disorders Hyperactive tendon reflexes Feeding problems during infancy Uplifted, flexed arms during walking Prominent mandible Increased sensitivity to heat Wide mouth, wide-spaced teeth Sleep disturbance Frequent drooling, protruding tongue Attraction to/fascination with water Excessive chewing/mouthing behaviors Flat back of head Smooth palms

Neurophysiology

Page 25: A Congenital Disorder

One of the more notable features of Angelman Syndrome (AS) is the syndrome’s pathognomonic neurophysiological findings. The electroencephalogram (EEG) in AS is usually very abnormal, and more abnormal than clinically expected.[11] Three distinct interictal patterns are seen in these patients (see Fig.).[12] The most common pattern is a very large amplitude 2–3 Hz rhythm most prominent in prefrontal leads (A). Next most common is a symmetrical 4–6 Hz high voltage rhythm (B). The third pattern, 3–6 Hz activity punctuated by spikes and sharp waves in occipital leads, is associated with eye closure (C). Paroxysms of laughter have no relation to the EEG, ruling out this feature as a gelastic phenomenon (Williams 2005).

Diagnosis

The diagnosis of Angelman syndrome is based on:

A history of delayed motor milestones and then later a delay in general development, especially of speech Unusual movements including fine tremors, jerky limb movements, hand flapping and a wide-based, stiff-

legged gait. Characteristic facial appearance (but not in all cases). A history of epilepsy and an abnormal EEG tracing. A happy disposition with frequent laughter A deletion or inactivity on chromosome 15 by array comparative genomic hybridization (aCGH) or by BACs-

on-Beads technology.

Diagnostic criteria for the disorder were initially established in 1995 in collaboration with the Angelman syndrome Foundation (USA);[13] these criteria have undergone revision in 2005.[14]

Treatment and care

There is currently no cure available. The epilepsy can be controlled by the use of one or more types of anticonvulsant medications. However, there are difficulties in ascertaining the levels and types of anticonvulsant medications needed to establish control, because AS is usually associated with having multiple varieties of seizures, rather than just the one as in normal cases of epilepsy. Many families use melatonin to promote sleep in a condition which often affects sleep patterns. Many individuals with Angelman syndrome sleep for a maximum of 5 hours at any one time. Mild laxatives are also used frequently to encourage regular bowel movements and early intervention with physiotherapy is important to encourage joint mobility and prevent stiffening of the joints.

Those with the syndrome are generally happy and contented people who like human contact and play. People with AS exhibit a profound desire for personal interaction with others. Communication can be difficult at first, but as a child with AS develops, there is a definite character and ability to make themselves understood. People with AS tend to develop strong non-verbal skills to compensate for their limited use of speech. It is widely accepted that their understanding of communication directed to them is much larger than their ability to return conversation. Most afflicted people will not develop more than 5-10 words, if any at all.[15]

Seizures are a consequence, but so is excessive laughter,[16] which is a major hindrance to early diagnosis.

Actor Colin Farrell,[17] author Ian Rankin,[18] professional baseball player Dave Henderson, and professional hockey player Peter McDuffe have sons with AS.[citation needed]

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Prognosis

The severity of the symptoms associated with Angelman syndrome varies significantly across the population of those affected. Some speech and a greater degree of self-care are possible among the least profoundly affected. Unfortunately, walking and the use of simple sign language may be beyond the reach of the more profoundly affected. Early and continued participation in physical, occupational (related to the development of fine-motor control skills), and communication (speech) therapies are believed to improve significantly the prognosis (in the areas of cognition and communication) of individuals affected by AS. Further, the specific genetic mechanism underlying the condition is thought to correlate to the general prognosis of the affected person. On one end of the spectrum, a mutation to the UBE3A gene is thought to correlate to the least affected, whereas larger deletions on chromosome 15 are thought to correspond to the most affected.

The clinical features of Angelman syndrome alter with age. As adulthood approaches, hyperactivity and poor sleep patterns improve. The seizures decrease in frequency and often cease altogether and the EEG abnormalities are less obvious. Medication is typically advisable to those with seizure disorders. Often overlooked is the contribution of the poor sleep patterns to the frequency and/or severity of the seizures. Medication may be worthwhile in order to help deal with this issue and improve the prognosis with respect to seizures and sleep. Also noteworthy are the reports that the frequency and severity of seizures temporarily escalate in pubescent Angelman syndrome girls but do not seem to affect long-term health.

The facial features remain recognizable but many adults with AS look remarkably youthful for their age.

Puberty and menstruation begin at around the average age. Sexual development is thought to be unaffected, as evidenced by a single reported case of a woman with Angelman syndrome conceiving a female child who also had Angelman syndrome.[19]

The majority of those with AS achieve continence by day and some by night. Angelman syndrome is not a degenerative syndrome. Many people with AS improve their living skills with support.

Dressing skills are variable and usually limited to items of clothing without buttons or zippers. Most adults are able to eat with a knife or spoon and fork and can learn to perform simple household tasks. General health is fairly good and life-span near average. Particular problems which have arisen in adults are a tendency to obesity (more in females), and worsening of scoliosis[20] if it is present. The affectionate nature which is also a positive aspect in the younger children may also persist into adult life where it can pose a problem socially, but this problem is not insurmountable.

AposthiaFrom Wikipedia, the free encyclopedia

Aposthia is a rare[quantify] congenital condition in humans, in which the foreskin of the penis is missing.

Toward the end of the nineteenth century, E. S. Talbot claimed in Medicine that aposthia among Jews was evidence for the now-discredited Lamarckian theory of evolution. It is likely that the cases he described were actually hypospadias, a condition in which the urinary meatus is on the underside of the penis. Neither condition has a particularly high incidence among Jews or Muslims

Page 27: A Congenital Disorder

Arnold–Chiari malformationFrom Wikipedia, the free encyclopedia

(Redirected from Arnold-Chiari malformation)

Arnold-Chiari

Classification and external resources

A T1-weighted sagittal MRI scan, from a patient with an Arnold-Chiari malformation, demonstrating tonsillar herniation of 7mm

ICD-10 Q 07.0

ICD-9 741.0

OMIM 207950

DiseasesDB 899

MeSH D001139

Arnold–Chiari malformation, or often simply Chiari malformation, is a malformation of the brain. It consists of a downward displacement of the cerebellar tonsils through the foramen magnum (the opening at the base of the skull), sometimes causing non-communicating [1] hydrocephalus as a result of obstruction of cerebrospinal fluid (CSF) outflow.[2] The cerebrospinal fluid outflow is caused by phase difference in outflow and influx of blood in the vasculature of the brain. It can cause headaches, fatigue, muscle weakness in the head and face, difficulty swallowing, dizziness, nausea, impaired coordination, and, in severe cases, paralysis.[3]

Contents

1 Classification 2 Symptoms

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3 Diagnosis 4 Treatment 5 Prognosis 6 Epidemiology 7 History 8 Society and culture

o 8.1 Notable cases 9 References 10 External links

Classification

The Austrian pathologist Hans Chiari in the late 19th century described seemingly related anomalies of the hindbrain, the so called Chiari malformations I, II and III. Later, other investigators added a fourth (Chiari IV) malformation. The scale of severity is rated I - IV, with IV being the most severe. Types III and IV are very rare.[4]

Type PresentationOther notes

IA congenital malformation. Is generally asymptomatic during childhood, but often manifests with headaches and cerebellar symptoms. Herniation of cerebellar tonsils.[5][6]

The most common form.

Syndrome of occipitoatlantoaxial hypermobility

An acquired Chiari I Malformation in patients with hereditary disorders of connective tissue.[7] Patients who exhibit extreme joint hypermobility and connective tissue weakness as a result of Ehlers-Danlos syndrome or Marfan Syndrome are susceptible to instabilities of the craniocervical junction and thus acquiring a Chiari Malformation. This type is difficult to diagnose and treat.[8]

II

Usually accompanied by a lumbar myelomeningocele[9] leading to partial or complete paralysis below the spinal defect. As opposed to the less pronounced tonsillar herniation seen with Chiari I, there is a larger cerebellar vermian displacement. Low lying torcular herophili, tectal beaking, and hydrocephalus with consequent clival hypoplasia are classic anatomic associations.[10] The position of the torcular herophili is important for distinction from Dandy-Walker syndrome in which it is classically upturned. This is important because the hypoplastic cerebellum of Dandy-Walker may be difficult to distinguish from a Chiari malformation that has herniated or is ectopic on imaging. Colpocephaly may be seen due to the associated neural tube defect.

IIICauses severe neurological defects. It is associated with an occipital encephalocele.[11]

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IV Characterized by a lack of cerebellar development.[12]

Other conditions sometimes associated with Chiari Malformation include hydrocephalus,[13]

syringomyelia, spinal curvature, tethered spinal cord syndrome, and connective tissue disorders[7] such as Ehlers-Danlos syndrome and Marfan Syndrome.

Chiari malformation is the most frequently used term for these types of malformations. The use of the term Arnold–Chiari malformation has fallen somewhat out of favor over time, although it is used to refer to the type II malformation. Current sources use "Chiari malformation" to describe four specific types of the condition, reserving the term "Arnold-Chiari" for type II only.[14] Some sources still use "Arnold-Chiari" for all four types.[15] This article uses the latter convention.

Chiari malformation or Arnold–Chiari malformation should not be confused with Budd-Chiari syndrome,[16] a hepatic condition also named for Hans Chiari.

Symptoms

Headaches aggravated by Valsalva maneuvers, such as yawning, laughing, crying, coughing, sneezing or straining[17]

Tinnitus (ringing in the ears) Dizziness and vertigo Nausea Nystagmus (irregular eye movements) Facial pain Muscle weakness Impaired gag reflex Restless Leg Syndrome Sleep Apnea Dysphagia (difficulty swallowing)[18]

Impaired coordination Dysautonomia: tachycardia (rapid heart), syncope (fainting), polydipsia (extreme thirst), chronic fatigue [19]

The blockage of Cerebro-Spinal Fluid (CSF) flow may also cause a syrinx to form, eventually leading to syringomyelia. Central cord symptoms such as hand weakness, dissociated sensory loss, and, in severe cases, paralysis may occur.[20]

Diagnosis

Diagnosis is made through a combination of patient history, neurological examination, and Magnetic Resonance Imaging (MRI). The radiographic criteria for diagnosing a congenital Chiari I Malformation is a downward herniation of the cerebellar tonsils greater than 5 mm below the foramen magnum. Other imaging techniques involve the use of 3-D CT imaging of the brain and cine imaging (a movie of the brain) can be used to determine if the brainstem is being compressed by the pulsating arteries that surround it.[21]

In the Syndrome of Occipitoatlantoaxial Hypermobility, cerebellar tonsillar herniation is typically only evident on an up-right MRI, due to the fact that the Chiari Malformation is gravitationally acquired by means of connective tissue weakness.[7] 3-D CT imaging may aid in the diagnosis of related disorders such

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as retroflexed odontoid. Invasive cranial traction (lifting of the head off the spine) is often used as a confirmation of the diagnosis.[22]

The diagnosis of a Chiari II Malformation can be made prenatally through Ultrasound.[23]

Treatment

Once symptomatic onset occurs, a common treatment is decompression surgery, [24] in which a neurosurgeon usually removes the lamina of the first and sometimes the second or even third cervical vertebrae and part of the occipital bone of the skull to relieve pressure. The flow of spinal fluid may be accompanied by a shunt. Since this surgery usually involves the opening of the dura mater and the expansion of the space beneath, a dural graft is usually applied to cover the expanded posterior fossa.

A small number of neurological surgeons believe that detethering the spinal cord as an alternate approach relieves the compression of the brain against the skull opening (foramen magnum), obviating the need for decompression surgery and associated trauma. However, this approach is significantly less documented in the medical literature, with reports on only a handful of patients. It should be noted that the alternative spinal surgery is also not without risk.[citation needed]

On April 24, 2009, a young patient with Type 1 Chiari malformation was successfully treated with a minimally invasive endoscopic transnasal procedure by Dr. Richard Anderson at the

Prognosis

The prognosis differs dependent on the type of malformation (i.e., type I, II, III, or IV). Type I is generally adult-onset and, while not curable, treatable and rarely fatal.[26] Syndrome of Occipitoatlantoaxial Hypermobility (Ehlers-Danlos syndrome related) is more difficult to treat than the congenital form of the disease. Individuals with this type do not respond well to the decompression surgery and often require an occipitoatlantoaxial fusion for stability.[7] These patients are at risk of experiencing serious heart complications.[27] Types I and II sufferers may also develop syringomyelia. Type II is typically diagnosed at birth or prenatally.[28] Approximately 33% of individuals with Chiari II malformation develop symptoms of brainstem damage within five years; a 1996 study found a mortality rate of 33% or more among symptomatic patients, with death frequently occurring due to respiratory failure.[29] 15% of individuals with Chiari II malformation die within two years of birth.[30] Among children under two who also have myelomeningocele, it is the leading cause of death.[31] Prognosis among children with Chiari II malformation who do not have spina bifida is linked to specific symptoms; the condition may be fatal among symptomatic children when it leads to neurological deterioration, but surgical intervention has shown promise.[32] Types III and IV are extremely rare and patients generally do not survive past the age of two or three.[33]

Epidemiology

The prevalence of Chiari 1 malformation, defined as tonsilar herniations of 3 to 5 mm or greater, is estimated to be in the range of one per 1000 to one per 5000 individuals.[7] The incidence of symptomatic Chiari is less but unknown.

History

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An Austrian pathologist, Hans Chiari, first described these hindbrain malformations in the 1890s.[34] A colleague of Professor Chiari, Dr. Julius Arnold, later contributed to the definition of the condition,[35] and students of Dr. Arnold (Schwalbe and Gredig)[36] suggested the term "Arnold-Chiari malformation" to henceforth refer to the condition.[37][38]

Some sources credit the characterization of the condition to Cleland[39][40] or Cruveilhier.[41]

Society and culture

The condition was brought to the mainstream on the series CSI in the tenth season episode "Internal Combustion" on February 4, 2010. Chiari was briefly mentioned in House, MD on the fifth season episode "House Divided" [42][43] and was the focus of the sixth season episode "The Choice." [44]

Bannayan–Riley–Ruvalcaba syndromeFrom Wikipedia, the free encyclopedia

(Redirected from Bannayan-Zonana syndrome)

Bannayan-Riley-Ruvalcaba syndrome

Classification and external resources

OMIM 153480

DiseasesDB 31337

MeSH D006223

Bannayan–Riley–Ruvalcaba syndrome (BRRS) is a rare hamartomatous disorder with occurrence of multiple subcutaneous lipomas, macrocephaly and hemangiomas.[1][2] The disease is inherited in an autosomal dominant form, but sporadic cases have been reported. The disease belongs to a family of hamartomatous polyposis syndromes, which also includes Peutz-Jeghers syndrome, juvenile polyposis and Cowden syndrome. Mutation of the PTEN gene underlies this syndrome, as well as Cowden syndrome, Proteus syndrome, and Proteus-like syndrome. Collectively, these four syndromes are referred to as PTEN Hamartoma-Tumor

Barth syndromeFrom Wikipedia, the free encyclopedia

Barth syndrome

Classification and external resources

Page 32: A Congenital Disorder

Cardiolipin

ICD-9 759.89

OMIM 302060

DiseasesDB 29297

MeSH D056889

Barth syndrome (BTHS), also known as 3-Methylglutaconic aciduria type II, is a X-linked[1] genetic disorder.

Contents

1 Presentation 2 Incidence 3 History 4 Cause 5 Barth Syndrome Foundation 6 See also 7 References 8 External links

Presentation

Though not always present, the cardinal characteristics of this multi-system disorder include: cardiomyopathy (dilated or hypertrophic, possibly with left ventricular noncompaction and/or endocardial fibroelastosis),[2][3] neutropenia (chronic, cyclic, or intermittent),[3] underdeveloped skeletal musculature and muscle weakness,[4] growth delay,[3] exercise intolerance, cardiolipin abnormalities,[5][6] and 3-methylglutaconic aciduria.[3]

It can be associated with stillbirth.[7]

Incidence

It has been documented in greater than 120 males to date (see Human Tafazzin (TAZ) Gene Mutation & Variation Database).[8] It is believed to be severely under-diagnosed[9] and may be estimated to occur in 1 out of approximately 300,000 births. Family members of the Barth Syndrome Foundation and its affiliates live in the US, Canada, the UK, Europe, Japan, South Africa, Kuwait, and Australia.

To date, Barth syndrome is found exclusively in males.

History

Page 33: A Congenital Disorder

The syndrome was named after Dr. Peter Barth (pediatric neurologist) in the Netherlands for his research and discovery in 1983.[4] He described a pedigree chart, showing that this is an inherited trait.

Cause

Mutations in the tafazzin gene (TAZ, also called G4.5) are closely associated with Barth syndrome. The tafazzin gene product is believed to function as an acyltransferase in complex lipid metabolism. [5][6] In 2008, Dr. Kulik found that all the BTHS individuals that he tested had abnormalities in their cardiolipin molecules, a lipid found inside the mitochondria of cells.[10] Cardiolipin is intimately connected with the electron transport chain proteins and the membrane structure of the mitochondria which is the energy producing organelle of the cell. The human tafazzin gene, NG_009634, is listed as over 10,000 base pairs in length, and the full-length mRNA, NM_000116, is 1919 nucleotides long encoding 11 exons with a predicted protein length of 292 amino acids and a molecular weight of 33.5 kDa. The tafazzin gene is located at Xq28;[11] the long arm of the X chromosome. Mutations in tafazzin that cause Barth syndrome span many different categories: missense, nonsense, deletion, frameshift, splicing (see Human Tafazzin (TAZ) Gene Mutation & Variation Database).[8]

iPLA2-VIA has been suggested as a target for treatment.[12]

Barth Syndrome Foundation

The Barth Syndrome Foundation (BSF), together with its affiliates, are the only worldwide volunteer organizations dedicated to saving lives through education, advances in treatment, and finding a cure for Barth syndrome. The Barth Syndrome Foundation sponsors a competitive Research Grant Program and International Conferences for affected families, attending physicians, and scientists every two years.

Nevoid basal cell carcinoma syndromeFrom Wikipedia, the free encyclopedia

(Redirected from Basal Cell Nevus syndrome)

Nevoid basal cell carcinoma syndrome

Classification and external resources

Micrograph showing keratocystic odontogenic tumour, a common finding in nevoid basal cell carcinoma syndrome. H&E stain.

Page 34: A Congenital Disorder

OMIM 109400

DiseasesDB 5370

eMedicine derm/291

MeSH C04.182.089.530.690.150

Nevoid basal cell carcinoma syndrome (NBCCS), also known as basal cell nevus syndrome, multiple basal cell carcinoma syndrome, Gorlin syndrome, and Gorlin–Goltz syndrome, is an inherited medical condition involving defects within multiple body systems such as the skin, nervous system, eyes, endocrine system, and bones.[1] People with this syndrome are particularly prone to developing a common and usually non-life-threatening form of non-melanoma skin cancers.

About 10% of people with the condition do not develop basal cell carcinomas (BCCs). the name Gorlin syndrome refers to researcher Robert J. Gorlin (1923–2006).[2]

First described in 1960, NBCCS is an autosomal dominant condition that can cause unusual facial appearances and a predisposition for basal cell carcinoma, a malignant type of skin cancer.[3] The prevalence is reported to be 1 case per 56,000-164,000 population. Recent work in molecular genetics has shown NBCCS to be caused by mutations in the PTCH (Patched) gene found on chromosome arm 9q.[4] If a child inherits the defective gene from either parent, he or she will have the disorder.

Contents

1 Incidence 2 Components 3 Diagnostic criteria 4 Treatment 5 See also 6 References 7 External links

Incidence

About 750,000 new cases of sporadic basal cell carcinomas (BCCs) occur each year in the United States. Ultraviolet (UV) radiation from the sun is the main trigger of these cancers, and people with fair skin are especially at risk. Most sporadic BCCs arise in small numbers on sun-exposed skin of people over age 50, although younger people may also be affected. By comparison, NBCCS has an incidence of 1 in 50,000 to 150,000 with higher incidence in Australia. One aspect of NBCCS is that basal cell carcinomas will occur on areas of the body which are not generally exposed to sunlight, such as the palms and soles of the feet and lesions may develop at the base of palmer and plantar pits. One of the prime features of NBCCS is development of multiple BCCs at an early age, often in the teen years. Each person who has this syndrome is affected to a different degree, some having many more characteristics of the condition than others.

Components

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Some or all of the following may be seen in someone with Gorlin Syndrome:

1. Multiple basal cell carcinomas of the skin2. Odontogenic keratocyst: Seen in 75% of patients and is the most common finding. There are usually

multiple lesions found in the mandible. They occur at a young age (19 yrs average).3. Rib and vertebrae anomalies4. Intracranial calcification5. Skeletal abnormalities: bifid ribs, kyphoscoliosis, early calcification of falx cerebri (diagnosed with AP

radiograph)6. Distinct faces: frontal and temporopariental bossing, hypertelorism, and mandibular prognathism

Diagnostic criteria

Diagnosis of NBCCS is made by having 2 major criteria or 1 major and 2 minor criteria. [2]

The major criteria consist of the following:

1. more than 2 BCCs or 1 BCC in a person younger than 20 years;2. odontogenic keratocysts of the jaw3. 3 or more palmar or plantar pits4. ectopic calcification or early (<20 years) calcification of the falx cerebri5. bifid, fused, or splayed ribs6. first-degree relative with NBCCS.

The minor criteria include the following:

1. macrocephaly.2. congenital malformations, such as cleft lip or palate, frontal bossing, eye anomaly (cataract, colobma,

microphtalmia, nystagmus).3. other skeletal abnormalities, such as Sprengel deformity, pectus deformity, polydactyly, syndactyly or

hypertelorism.4. radiologic abnormalities, such as bridging of the sella turcica, vertebral anomalies, modeling defects or

flame-shaped lucencies of hands and feet.5. ovarian and cardio fibroma or medulloblastoma (the latter is generally found in children below the age of

two).

People with NBCCS need education about the syndrome, and may need counseling and support, as coping with the multiple BCCs and multiple surgeries is often difficult. They should reduce UV light exposure, to minimize the risk of BCCs. They should also be advised that receiving Radiation therapy for their skin cancers may be contraindicated. They should look for symptoms referable to other potentially involved systems: the CNS, the genitourinary system, the cardiovascular system, and dentition.

Genetic counseling is advised for prospective parents, since one parent with NBCCS causes a 50% chance that their child will also be affected.

Treatment

Treatment is usually supportive treatment, that is, treatment to reduce any symptoms rather than to cure the condition.

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Enucleation of the odontogenic cysts can help but new lesions, infections and jaw deformity are usually a result.

The severity of the basal cell carcinoma determines the prognosis for most patients. BCCs rarely cause gross disfigurement, disability or death [3].

Genetic counseling

Beckwith–Wiedemann syndromeFrom Wikipedia, the free encyclopedia

(Redirected from Beckwith-Wiedemann syndrome)

Beckwith-Wiedemann syndrome

Classification and external resources

ICD-10 Q 87.3

ICD-9 759.89

OMIM 130650

DiseasesDB 14141

eMedicine ped/218

MeSH C16.131.077.133

Beckwith–Wiedemann syndrome (BWS) is an overgrowth disorder present at birth characterized by an increased risk of childhood cancer and certain features. Originally, Dr. Hans-Rudolf Wiedemann coined the term exomphalos-macroglossia-gigantism (EMG) syndrome to describe the combination of congenital hernia - exomphalos, large tongue - macroglossia, and large body (and/or long limbs) - gigantism. Over time, this constellation was renamed Beckwith–Wiedemann syndrome. Five common features used to define BWS are: macroglossia, macrosomia - (birth weight and length >90th percentile), midline abdominal wall defects (omphalocele, umbilical hernia, diastasis recti), ear creases or ear pits, and neonatal hypoglycemia (low blood sugar after birth).[1]

Contents

1 Presentation 2 Occurrence 3 Genetics 4 Management 5 Neoplasms 6 Prognosis 7 Assisted reproductive technology 8 History 9 See also 10 References

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11 External links

Presentation

Most children with BWS do not have all of these five features. In addition, some children with BWS have other findings including: nevus flammeus, prominent occiput, midface hypoplasia, hemihypertrophy, genitourinary anomalies (enlarged kidneys), cardiac anomalies, musculoskeletal abnormalities, and hearing loss. Also, some premature newborns with BWS do not have macroglossia until closer to their anticipated delivery date.[2]

Given the variation among individuals with BWS and the lack of a simple diagnostic test, identifying BWS can be difficult. In an attempt to standardize the classification of BWS, DeBaun et al. have defined a child as having BWS if the child has been diagnosed by a physician as having BWS and if the child has at least two of the five common features associated with BWS (macroglossia, macrosomia, midline abdominal wall defects, ear creases/ear pits, neonatal hypoglycemia).[3] Another definition presented by Elliot et al. includes the presence of either three major features (anterior abdominal wall defect, macroglossia, or prepostnatal overgrowth) or two major plus three minor findings (ear pits, nevus flammeus, neonatal hypoglycemia, nephromegaly, or hemihyperplasia).[4]

While most children with BWS do not develop cancer, children with BWS do have a significantly increased risk of cancer. Children with BWS are most at risk during early childhood and should receive cancer screening during this time.

In general, children with BWS do very well and grow up to become adults of normal size and intelligence, usually without the syndromic features of their childhood.

Occurrence

Beckwith–Wiedemann syndrome has an estimated incidence of one in 13,700; about 300 children with BWS are born each year in the United States.[5] The exact incidence of BWS is unknown because of the marked variability in the syndome's presentation and difficulties with diagnosis. The number of reported infants born with BWS is most likely low because many are born with BWS, but have clinical features that are less prominent and therefore missed. BWS has been documented in a variety of ethnic groups and occurs equally in males and females.

Children conceived through In vitro fertilization have a three to fourfold increased chance of developing Beckwith–Wiedemann syndrome. It is thought that this is due to genes being turned on or off by the IVF procedures.

Genetics

Most (>85%) cases of BWS are sporadic, meaning that usually no one else in that family has BWS and parents of an affected child are not at increased risk of having other children with BWS. However, some

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(<15%) cases of BWS are familial, meaning that someone else in that family may also have BWS and parents of an affected child may be at increased risk of having other children with BWS. BWS has been shown to specifically involve problems with a defined region on the short arm of chromosome 11 referred to as 11p15. This region contains genes that are imprinted. Imprinted genes are unique in that they are expressed differently depending on whether they came from the mother (maternal copy) or father (paternal copy). Most genes are not imprinted and both the maternal and paternal copies of the gene are actively expressed. In imprinted genes, only one parental copy is active; the other copy is silent. In some imprinted genes only the maternal copy is active, while in other cases only the paternal copy is active.

BWS can be caused by a range of different genetic defects. Over five distinct errors involving 11p15 have been identified in different BWS patients. Some patients have maternal chromosomal rearrangements of 11p15, meaning that there is a disruption of the chromosome in this region. Other patients have paternal uniparental disomy (UPD) of 11p15, meaning that the maternal copy of this region is replaced with an extra paternal copy. Many other patients have abnormal DNA methylation in different areas of 11p15, meaning that normal epigenetic marks that regulate imprinted genes in this region are altered. A few other patients have a single gene located within 11p15.

Additionally, even after extensive molecular testing, the specific defect causing BWS in an affected individual may remain unknown. In about 1/3 of BWS patients, the genetic or epigenetic mutation is unknown. This fact demonstrates why BWS remains a clinical diagnosis because physicians cannot identify and test for all the genetic causes of BWS. The clinical definition used for BWS is limited because no standard diagnostic criteria exist that have been independently verified with patients who have either genetic or epigenetic mutations. When molecular analyses were completed in children who met a research criteria for BWS, only 7 of 10 children had genetic or epigenetic mutations. [3] The absence of a mutation in a child with clinical findings suggestive of BWS should not preclude a diagnosis of BWS.

Given that the genetics of BWS are complex, a child with BWS should be under the medical care of a geneticist or an expert in the management of BWS.

Genes involved are IGF2, p57, CDKN1C, H19, and LIT1.[8]

Management

Abdominal wall defects are common in newborns with BWS and may require surgical treatment. These defects can range in severity from omphalocele (most serious) to umbilical hernia and diastasis recti (least serious). An omphalocele is a congenital malformation in which a newborn's intestines, and sometimes other abdominal organs, protrude out of the abdomen through the umbilicus. Newborns with an omphalocele typically require surgery to place the abdominal contents back into the abdomen in order to prevent serious infection or shock. An umbilical hernia is also a defect in which abdominal contents come through weak abdominal wall muscle at the umbilicus. In general, newborns with umbilical hernias do not require treatment because often these hernias spontaneously close by age four. If, after this time, a hernia is still present, surgery may be recommended. Diastasis recti is a separation of the left and right sides of the rectus abdominis muscle that are normally joined together. Children with diastasis recti usually require no treatment because the condition resolves as the child grows.

Neonatal hypoglycemia, low blood glucose in the first month of life, occurs in about half of children with BWS.[9] Most of these hypoglycemic newborns are asymptomatic and have a normal blood glucose level within days. However, untreated persistent hypoglycemia can lead to permanent brain damage. Hypoglycemia in newborns with BWS should be managed according to standard protocols for treating

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neonatal hypoglycemia. Usually this hypoglycemia can easily be treated with more frequent feedings or medical doses of glucose. Rarely (<5%) children with BWS will continue to have hypoglycemia after the neonatal period and require more intensive treatment.[3] Such children may require tube feedings, oral hyperglycemic medicines, or a partial pancreatectomy.

Macroglossia, a large tongue, is a very common (>90%) and prominent feature of BWS. Infants with BWS and macroglossia typically cannot fully close their mouth in front of their large tongue, causing it to protrude out. Macroglossia in BWS becomes less noticeable with age and often requires no treatment; but it does cause problems for some children with BWS. In severe cases, macroglossia can cause respiratory, feeding, and speech difficulties. Children with BWS and significant macroglossia should be evaluated by a craniofacial team.

The best time to perform surgery for a large tongue is not known. Some surgeons recommend performing the surgery between 3 and 6 months of age. Surgery for macroglossia involves removing a small part of the tongue so that it fits within the mouth to allow for proper jaw and tooth development.

Nevus flammeus (port-wine stain) is a flat, red birthmark caused by a capillary (small blood vessel) malformation. Children with BWS often have nevus flammeus on their forehead or the back of their neck. Nevus flammeus is benign and commonly does not require any treatment.

Hemihypertrophy (hemihyperplasia) is an abnormal asymmetry between the left and right sides of the body occurring when one part of the body grows faster than normal. Children with BWS and hemihypertrophy can have an isolated asymmetry of one body part, or they can have a difference affecting the entire one side of the body. Individuals who do not have BWS can also have hemihypertrophy. Isolated hemihypertrophy is associated with a higher risk for cancer. [10] The types of cancer and age of the cancers are similar to children with BWS. As a result children with hemihypertrophy should follow the general cancer screening protocol for BWS.

Hemihypertrophy can also cause various orthopedic problems, so children with significant limb hemihyperplasia should be evaluated and followed by an orthopedic surgeon.

Finally hemihyperplasia affecting the face can sometimes cause significant cosmetic concerns that may be addressed by a cranial facial team.

Neoplasms

Most children (>80%) with BWS do not develop cancer; however, children with BWS are much more likely (~600 times more) than other children to develop certain childhood cancers, particularly Wilms' tumor (nephroblastoma) and hepatoblastoma.[1] Individuals with BWS appear to only be at increased risk for cancer during childhood (especially before age four) and do not have an increased risk of developing cancer in adulthood.[1] If 100 children with BWS were followed from birth until age ten, about 10 cases of cancer would be expected in the group before age four, and about 1 case of cancer in the group would be expected between age four and ten.

In addition to Wilms tumor and hepatoblastoma, children with BWS are also at increased risk of developing adrenal cortical carcinoma, neuroblastoma, and rhabdomyosarcoma.

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Both Wilms tumor and hepatoblastoma can usually be cured if diagnosed early. Early diagnosis allows physicians to treat the cancer when it is at an early stage. In addition, there is less toxic treatment. [11] Given the importance of early diagnosis, all children with BWS should receive cancer screening.

An abdominal ultrasound to every 3 months until at least eight years of age is recommended [11] and a blood test to measure alpha-fetoprotein (AFP) every 6 weeks until at least four years of age. [12] Families and physicians should determine screening schedules for specific patients, especially the age at which to discontinue screening, based upon their own evaluation of the risk-benefit ratio.

Prognosis

In general, the prognosis is very good. Children with BWS usually do very well and grow up to become the heights expected based on their parents heights. While children with BWS are at increased risk of childhood cancer, most children with BWS do not develop cancer and the vast majority of children who do develop cancer can be treated successfully.

Children with BWS for the most part had no significant delays when compared to their siblings. However, some children with BWS do have speech problems that could be related to macroglossia or hearing loss.

Advances in treating neonatal complications and premature infants in the last twenty years have significantly improved the true infant mortality rate associated with BWS. In a review of pregnancies that resulted in 304 children with BWS, not a single neonatal death was reported.[13] This is compared to a previously reported mortality rate of 20%.[14] The data from the former study was derived from a BWS registry, a database that may be slightly biased towards involving living children; however, death was not an exclusion criterion to join the registry. This suggests that while infants with BWS are likely to have a higher than normal infant mortality risk, it may not be as high as 20%.

Assisted reproductive technology

Assisted reproductive technology (ART) is a general term referring to methods used to achieve pregnancy by artificial or partially artificial means. According to the CDC, in general, ART procedures involve surgically removing eggs from a woman's ovaries, combining them with sperm in the laboratory, and returning them to the woman's body or donating them to another woman. ART has been associated with epigenetic syndromes, specifically BWS and Angelman syndrome. Three groups have shown an increased rate of ART conception in children with BWS.[3][15][16][17] A retrospective case control study from Australia found a 1 in 4000 risk of BWS in their in-vitro population, several times higher than the general population.[18] Another study found that children conceived by in vitro fertilisation (IVF) are three to four times more likely to develop the condition.[19] No specific type of ART has been more closely associated with BWS.[17] The mechanism in which ART produces this effect is still under investigation.

History

In the 1960s, Dr. J. Bruce Beckwith, an American pathologist and Dr. Hans-Rudolf Wiedemann, a German pediatrician, independently reported cases of a proposed new syndrome. [20][21] Originally termed EMG syndrome (for exomphalos, macroglossia, and gigantism), this syndrome over time became known as Beckwith–Wiedemann syndrome or Wiedemann Beckwith syndrome.

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Benjamin syndromeFrom Wikipedia, the free encyclopedia

For Harry Benjamin syndrome, see Transsexualism#Alternative terminology.

Benjamin Syndrome (or Benjamin anemia) is a type of multiple congenital anomaly/mental retardation (MCA/MR) syndrome. It is characterized by hypochromic anemia with mental deficiency and various craniofacial and other anomalies.[1] It can also include heart murmur, dental caries and splenic tumors.[2]

It was first described in the medical literature in 1911.[3] Symptoms include megalocephaly, external ear deformities, dental caries, micromelia, hypoplastic bone deformities, hypogonadism, hypochromic anemia with occasional tumors, and mental retardation.[4]

Benjamin Syndrome should not be confused with Harry Benjamin syndrome which is a separate and unrelated term.

Bladder exstrophyFrom Wikipedia, the free encyclopedia

Bladder exstrophy

Classification and external resources

ICD-10 Q 64.1

ICD-9 753.5

OMIM 600057

DiseasesDB 33377

eMedicine ped/704

MeSH C12.740.700.132

Bladder exstrophy is a congenital anomality in which part of the urinary bladder is present outside the body. It is rare, occurring once every 10,000 to 50,000 live births with a 2:1 male:female ratio. The diagnosis involves a spectrum of anomalies of the lower abdominal wall, bladder, anterior bony pelvis, and external genitalia. It occurs due to failure of the abdominal wall to close during fetal development and results in protrusion of the posterior bladder wall through the lower abdominal wall.

Treatment is with surgical correction of the defect, but patients can still have long term issues with urinary tract infections and urinary incontinence.

Contents

1 Pathogenesis

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2 Spectrum of anomalies 3 Diagnosis 4 Evaluation and Management at Birth 5 Treatment 6 Prognosis 7 Support groups 8 References 9 External links

Pathogenesis

The cause of bladder exstrophy is maldevelopment of the lower abdominal wall, leading to a rupture which causes the bladder to communicate with the amniotic fluid.

Spectrum of anomalies

The typical manifestation of exstrophy-epispadias complex is

bladder everted through a midline lower abdominal wall defect widening of the pubic symphysis epispadias in males (dorsal cleft in the penis, exposing the urethral mucosa) the anus and vagina appear anteriorly displaced the testicles may be undescended. bifid clitoris in females, with a short "urethral strip" indistinguishable from bladder mucosa.

The spectrum of disease extends from spade penis and epispadias on one hand, to exstrophy with cloaca (also known as cloacal exstrophy).

Diagnosis

Prenatal diagnosis of bladder extrophy is difficult and sometimes impossible. Feature on prenatal ultrasound can include the absence of bladder filling, a low-set umbilicus, widening of the pubic ramus, small external genetalia and a lower abdominal mass. Most often the diagnosis is made after birth with the finding of an exposed bladder. It can be found if they notice during ultrasound that the bladder is small.

Evaluation and Management at Birth

At birth, the bladder mucosa is exposed and is quite sensitive. The umbilical cord should be tied with a 2-0 silk suture rather than a clamp to prevent trauma to the delicate mucosa. In addition, the bladder should be covered with a non-adherent film (Plastic Wrap) to prevent sticking of the bladder to diapers or clothing. With each diaper change the plastic wrap should be removed and the bladder irrigated with sterile saline and a clean wrap should be placed. The child should then be transferred to a tertiary care pediatric hospital for management of their bladder exstrophy.

Treatment

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Modern therapy is aimed at surgical reconstruction of the bladder and genitalia, most often through a staged approach. The initial surgical management consists of bladder, posterior urethral and abdominal wall closure (with or without osteotomies). Bladder closure may be delayed if the bladder is deemed too small to close. The surgical management epispadius usually occurs at approximately 6-12 months of age. Reconstruction of the bladder neck is typically done at toilet training age (approximately age 4-5), once the child is able to and interested in participating in a bladder retraining program. In very carefully selected patients surgical management may be carried out in a single stage or in combined procedures.

Prognosis

Even with successful surgery, patients may have long-term problems with[1]

incontinence urinary reflux (see Vesicoureteral_reflux) repeated urinary tract infections bladder adenocarcinoma colonic adenocarcinoma self-image uterine prolapse

Sexual function and libido are normal in exstrophy patients. Successful pregnancies and delivery in exstrophy patients have been reported.

Bloom syndromeFrom Wikipedia, the free encyclopedia

Bloom syndrome

Classification and external resources

ICD-9 757.39

OMIM 210900

DiseasesDB 1505

eMedicine derm/54

MeSH D001816

Bloom syndrome (BLM),[1] also known as Bloom–Torre–Machacek syndrome,[2]:575 is a rare autosomal recessive[3] chromosomal disorder characterized by a high frequency of breaks and rearrangements in an affected person's chromosomes. The condition was discovered and first described by dermatologist Dr. David Bloom in 1954.[4]

Contents

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1 Presentation 2 Relationship to cancer 3 Pathophysiology 4 Other mutations in Bloom Syndrome 5 PKM2(M2-PK); A potential multi-functional protein 6 See also 7 References 8 External links

Presentation

Bloom syndrome is characterized by short stature and a facial rash that develops shortly after first exposure to sun. This rash can make a butterfly-shaped patch of reddened skin on the cheeks. The rash can develop on other sun-exposed areas such as the backs of the hands. Other clinical features include a high-pitched voice; distinct facial features, such as a long, narrow face, micrognathism of the mandible, and prominent nose and ears; pigmentation changes of the skin including hypo- and hyper-pigmented areas and cafe-au-lait spots; telangiectasias (dilated blood vessels) which can appear on the skin but also in the eyes; moderate immune deficiency, characterized by deficiency in certain immunoglobulin classes, that apparently leads to recurrent pneumonia and ear infections; hypo-gonadism characterized by a failure to produce sperm, hence infertility in males, and premature cessation of menses (premature menopause), hence sub-fertility in females. However, several women with Bloom syndrome have had children.

Complications of the disorder may include chronic lung problems, diabetes, and learning disabilities. In a small number of persons, there is mental retardation. The most striking complication of the disorder is susceptibility to cancer, as described in more detail in the next section.

Relationship to cancer

A greatly elevated rate of mutation in Bloom syndrome results in a high risk of cancer in affected individuals.[5] The cancer predisposition is characterized by 1) broad spectrum, including leukemias, lymphomas, and carcinomas, 2) early age of onset relative to the same cancer in the general population, and 3) multiplicity.[6] Persons with Bloom syndrome may develop cancer at any age. The average age of cancer diagnoses in the cohort is approximately 25 years old.

Pathophysiology

Mutations in the BLM gene, which is a member of the DNA helicase family, are associated with Bloom syndrome. DNA helicases are enzymes that unwind the two strands of a duplex DNA molecule. DNA unwinding is required for most processes that involve the DNA, including synthesis of DNA copies, RNA transcription, DNA repair, etc.

When a cell prepares to divide to form two cells, the chromosomes are duplicated so that each new cell will get a complete set of chromosomes. The duplication process is called DNA replication. Errors made during DNA replication can lead to mutations. The BLM protein is important in maintaining the stability of the DNA during the replication process. The mutations in the BLM gene associated with Bloom syndrome inactivate the BLM protein's DNA helicase activity or nullify protein expression (the protein is

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not made). Lack of BLM protein or protein activity leads to an increase mutations; however, the molecular mechanism(s) by which BLM maintains stability of the chromosomes is still a very active area of research.

Persons with Bloom syndrome have an enormous increase in exchange events between homologous chromosomes or sister chromatids (the two DNA molecules that are produced by the DNA replication process); and there are increases in chromosome breakage and rearrangements compared to persons who do not have Bloom syndrome. Direct connections between the molecular processes in which BLM operates and the chromosomes themselves are under investigation. The relationships between molecular defects in Bloom syndrome cells, the chromosome mutations that accumulate in somatic cells (the cells of the body), and the many clinical features seen in Bloom syndrome are also areas of intense research.

Bloom syndrome has an autosomal recessive pattern of inheritance.

Bloom syndrome is inherited in an autosomal recessive fashion. Both parents must be carriers in order for a child to be affected. The carrier frequency in individuals of Eastern European Jewish (Ashkenazi Jewish) ancestry is about 1/100. If both parents are carriers, there is a one in four, or 25%, chance with each pregnancy for an affected child. Genetic counseling and genetic testing is recommended for families who may be carriers of Bloom syndrome. For families in which carrier status is known, prenatal testing is available using cytogenetic or molecular methods. Molecular DNA testing for the mutation that is common in the Ashkenazi Jewish population is also available.

Other mutations in Bloom Syndrome

For the first time pyruvate kinase M2 enzyme was reported with two missense mutations, H391Y and K422R, found in cells from Bloom syndrome patients, prone to develop cancer. Results show that despite the presence of mutations in the inter-subunit contact domain, the K422R and H391Y mutant proteins maintained their homotetrameric structure, similar to the wild-type protein, but showed a loss of activity of 75 and 20%, respectively. Interestingly, H391Y showed a 6-fold increase in affinity for its substrate phosphoenolpyruvate and behaved like a non-allosteric protein with compromised cooperative binding. However, the affinity for phosphoenolpyruvate was lost significantly in K422R. Unlike K422R, H391Y showed enhanced thermal stability, stability over a range of pH values, a lesser effect of the allosteric inhibitor Phe, and resistance toward structural alteration upon binding of the activator (fructose 1,6-

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bisphosphate) and inhibitor (Phe). Both mutants showed a slight shift in the pH optimum from 7.4 to 7.0. [7]

The co-expression of homotetrameric wild type and mutant PKM2 in the cellular milieu resulting in the interaction between the two at the monomer level was substantiated further by in vitro experiments. The cross-monomer interaction significantly altered the oligomeric state of PKM2 by favoring dimerisation and heterotetramerization. In silico study provided an added support in showing that hetero-oligomerization was energetically favorable. The hetero-oligomeric populations of PKM2 showed altered activity and affinity, and their expression resulted in an increased growth rate of Escherichia coli as well as mammalian cells, along with an increased rate of polyploidy. These features are known to be essential to tumor progression.[8]