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45-825: No consensus clinical diagnostic criteria for Beckwith–Wiedemann syndrome (BWS) exist. Beckwith–Wiedemann syndrome (BWS) should be suspected in individuals who have one or more of the following major and/or minor findings. Major findings associated with BWS Minor findings associated with BWS The diagnosis of BWS is established in a proband with either of the following: Most children with BWS do not have all of these 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. Given

90-514: A 1 in 4000 risk of BWS in their in-vitro population, several times higher than the general population. Another study found that children conceived by in vitro fertilisation ( IVF ) are three to four times more likely to develop the condition. No specific type of ART has been more closely associated with BWS. The mechanism by which ART produces this effect is still under investigation. Beckwith–Wiedemann syndrome has an estimated incidence of one in 13,700; about 300 children with BWS are born each year in

135-403: A confirmatory histological investigation is done. 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

180-526: 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. These children are often managed by a multidisciplinary craniofacial team. These teams include speech and language therapists , craniofacial and paediatric plastic surgeons , and orthodontists who decide

225-432: A defect known as Beckwith-Weidemann Syndrome. Beckwith-Weidemann Syndrome (BWS) may also be brought about by CDKN1C 11p15 epimutations. It may also be a result of deletions of small amounts of DNA that cause chromosomal abnormalities, rendering the gene inactive. This leaves only the paternally expressed IGF2 to promote cell proliferation. The reduction of growth restriction results in the overgrowth of many tissues, leading to

270-570: A defined region on the short arm of chromosome 11 referred to as 11p15.5, that leads to overactivity of the IGF-2 gene (growth factor) and/or no active copy of CDKN1C (inhibitor of cell proliferation gene). BWS can be caused by a range of different genetic defects. Over five distinct errors involving 11p15.5 have been identified in different BWS patients. Some patients have maternal chromosomal rearrangements of 11p15.5. Other patients have paternal uniparental disomy (UPD) of chromosome 11, meaning that

315-528: A diagnosis of BWS. Even after extensive molecular testing, the specific defect causing BWS in an affected individual may remain unknown. BWS remains a clinical, rather than genetic, diagnosis, since 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 10 children who met

360-568: 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. 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. Hemihyperplasia affecting

405-461: 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. 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. Most of these hypoglycemic newborns are asymptomatic and have

450-507: A negative regulator of cell proliferation, effectively making CDKN1C a tumor suppressor gene. CDKN1C also works during fetal development, preventing the fetus from becoming too large. It is located on the short arm of the human chromosome 11 in the ICR2 region, along with many other imprinted genes. Since CDKN1C is preferentially maternally expressed, hypomethylation in the ICR2 region of the maternal allele can result in pathologies such as cancer or

495-420: 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 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

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540-665: A person receives two copies of a chromosome , or of part of a chromosome, from one parent and no copy from the other. UPD can be the result of heterodisomy, in which a pair of non-identical chromosomes are inherited from one parent (an earlier stage meiosis I error) or isodisomy , in which a single chromosome from one parent is duplicated (a later stage meiosis II error). Uniparental disomy may have clinical relevance for several reasons. For example, either isodisomy or heterodisomy can disrupt parent-specific genomic imprinting , resulting in imprinting disorders. Additionally, isodisomy leads to large blocks of homozygosity , which may lead to

585-411: A port-wine stain based entirely upon the history and appearance. In unusual cases, a skin biopsy may be needed to confirm the diagnosis. Depending on the location of the birthmark and other associated symptoms, a physician may choose to order a measurement of intraocular pressure or X-ray of the skull . An MRI of the brain may be performed (under anesthesia) on infants who have a port-wine stain in

630-406: A research criterion for BWS, only 7 of the 10 children had genetic or epigenetic mutations. Given that the genetics of BWS are complex, a child with BWS should be offered the medical care of a geneticist or an expert in the management of BWS. Genes involved are IGF-2 , CDKN1C , H19 , and KCNQ1OT1 . CDKN1C is a protein-coding gene that encodes a cyclin-dependent kinase inhibitor that acts as

675-399: A severe increase in the size of the adrenal glands in some of these patients. Nevus flammeus A port-wine stain ( nevus flammeus ) is a discoloration of the human skin caused by a vascular anomaly (a capillary malformation in the skin). They are so named for their coloration, which is similar in color to port wine , a fortified red wine from Portugal . A port-wine stain

720-693: 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. In the 1960s, Dr. John Bruce Beckwith , an American pathologist and Dr. Hans-Rudolf Wiedemann , a German pediatrician, independently reported cases of a proposed new syndrome. Originally termed EMG syndrome (for exomphalos , macroglossia , and gigantism ), this syndrome over time became known as Beckwith–Wiedemann syndrome or Wiedemann Beckwith syndrome. Originally, Dr. Hans-Rudolf Wiedemann (born 16 February 1915, Bremen, Germany, died 4 August 2006, Kiel) coined

765-456: Is a capillary malformation, seen at birth . Port-wine stains persist throughout life. The area of skin affected grows in proportion to general growth. Port-wine stains occur most often on the face but can appear anywhere on the body, particularly on the neck, upper trunk, arms and legs. Early stains are usually flat and pink in appearance. As the child matures, the color may deepen to a dark red or purplish color. In adulthood, thickening of

810-514: 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

855-615: 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. A retrospective case control study from Australia found

900-443: Is compared to a previously reported mortality rate of 20%. 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 (ART)

945-419: Is when all chromosomes are inherited from one parent. Only in mosaic form can this phenomenon be compatible with life. As of 2017, there have only been 18 reported cases of genome wide UPD. Eric Engel first proposed the concept of uniparental disomy in 1980 as both homologous chromosomes are inherited from one parent, with no contribution (for that chromosome) from the other parent. Eight years later in 1988,

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990-572: The UPD-causing event happened during meiosis II, the genotype may include identical copies of the uniparental chromosome (isodisomy), leading to the manifestation of rare recessive disorders. UPD should be suspected in an individual manifesting a recessive disorder where only one parent is a carrier . Uniparental inheritance of imprinted genes can also result in phenotypical anomalies. Although few imprinted genes have been identified, uniparental inheritance of an imprinted gene can result in

1035-540: The United States. The exact incidence of BWS is unknown because of the marked variability in the syndrome'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

1080-467: 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,

1125-549: The age at which to discontinue screening, based upon their own evaluation of the risk-benefit ratio. Most (>85%) cases of BWS are sporadic, meaning that, typically, 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 (<15%) cases of BWS are familial, meaning that a close relative 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 mutations in

1170-519: The appropriateness and timing of tongue reduction surgery. Some countries have designated centres for the management of macroglossia. For example, in the United Kingdom , children who have macroglossia associated with Beckwith Wiedemann Syndrome are managed in a national specialised service. The service is commissioned as highly specialised service by NHS England and is located at Great Ormond Street Hospital . Nevus flammeus (port-wine stain)

1215-470: The cancer when it is at an early stage. In addition, there is less toxic treatment. Given the importance of early diagnosis, all children with BWS should be offered cancer screening. An abdominal ultrasound every 3 months until at least eight years of age is recommended and a blood test to measure alpha-fetoprotein (AFP) every 6 weeks until at least four years of age. Families and physicians should determine screening schedules for specific patients, especially

1260-438: The common symptoms of BWS. These symptoms may include macroglossia, organomegaly, periorbital fullness, and hernias. Knockout models for CDKN1C in mice do exist; in fact, many of the affected offspring exhibit fetal and neonatal lethality and have most of the features related to Beckwith-Weidemann Syndrome. Diagnosis is usually clinical and lab inclined. If the clinical features commonly associated with this syndrome are identified

1305-456: The face can sometimes cause significant cosmetic concerns that may be addressed by a cranial facial team. 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 they are at increased risk of childhood cancer, most of them do not develop the disease, and the vast majority of the children who do can be treated successfully. Children with BWS for

1350-542: 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 have been shown in individual case reports to develop ganglioneuroma , adrenocortical carcinoma , acute lymphoid leukemia , liver sarcoma , thyroid carcinoma , melanoma , rhabdomyosarcoma , and mesoblastic nephroma . Wilms tumor, hepatoblastoma, and mesoblastic nephroma can usually be cured if diagnosed early. Early diagnosis allows physicians to treat

1395-454: The head area in order to check for signs of Sturge–Weber syndrome . If the port-wine stain is inside the mouth, a provider may check the insides of a newborn baby's throat with a scope to see if there are any changes (growths) other than just the color. If the port-wine stain is around the eye or on the eyelid, a referral may be made to an optometrist or ophthalmologist for a test of the ocular pressures in that eye. If swelling occurs in

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1440-476: The lesion or the development of small lumps may occur. Port-wine stains may be part of a syndrome such as Sturge–Weber syndrome or Klippel–Trénaunay–Weber syndrome . Nevus flammeus may be divided as follows: Port-wine stains were shown to be caused by a somatic activating c.548G→A mutation in the GNAQ gene. An association with RASA1 has also been described. A healthcare provider can usually diagnose

1485-399: The loss of gene function, which can lead to delayed development, intellectual disability, or other medical problems. UPD has rarely been studied prospectively, with most reports focusing on either known conditions or incidental findings. It has been proposed that the incidence may not be as low as believed, rather it may be under-reported. Genome wide UPD, also called uniparental diploidy,

1530-447: The maternal copy of this chromosome is replaced with an extra paternal copy. Many other patients have abnormal DNA methylation in different areas of 11p15.5, meaning that normal epigenetic marks that regulate imprinted genes in this region are altered. A few other patients have a single gene copy located within 11p15, instead of two copies. The absence of a mutation in a child with clinical findings suggestive of BWS should not preclude

1575-452: The most part had no significant delays when compared to their siblings. However, some of them 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, no neonatal deaths were reported. This

1620-730: The neonatal period and require more intensive treatment. 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

1665-412: The port-wine stain, it may cause vision problems, glaucoma , or blindness . Many treatments have been tried for port-wine stains including freezing, surgery , radiation , and tattooing ; port-wine stains can also be covered with cosmetics . Lasers may be able to destroy the capillaries without significant damage to the overlying skin. Lasers and other light sources may therefore be able to reduce

1710-974: The presence of either three major features (anterior abdominal wall defect, macroglossia, or prepostnatal overgrowth) or two major plus three minor findings (ear creases, nevus flammeus, neonatal hypoglycemia, nephromegaly, or hemihyperplasia). 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. 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), pancreatoblastoma, and hepatoblastoma . 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. If 100 children with BWS were followed from birth until age ten, about 10 cases of cancer would be expected in

1755-431: The redness of port-wine stains, although there is not enough evidence to recommend one form over another. For most people in trials of pulsed dye laser , more than 25% of the redness was reduced by laser after one to three treatments. Adverse effects were rare in these trials, although some people had changes to the color of the skin, especially Chinese people with darker skin. There can be pain, crusting, and blistering in

1800-418: The size of a pen. This is due to the laser instrument's size; the black marks disappear within 1–3 weeks. The treated area can be sore and swollen for a couple of days. However, with newer v-beam laser treatments, there may not be any marks at all. In the absence of successful treatment, hypertrophy (increased tissue mass) of the stains may cause problems later in life, such as loss of function (especially if

1845-673: The stain is near the eye or mouth), bleeding, and increasing disfigurement . Lesions on or near the eyelid can be associated with glaucoma . If the port-wine stain is on the face or other highly visible part of the body, its presence can also cause emotional and social problems for the affected person. Studies have recorded an incidence of about 3–5 cases per 1,000 newborn babies. see also Template:Congenital malformations and deformations of skin appendages , Template:Phakomatoses , Template:Pigmentation disorders , Template:DNA replication and repair-deficiency disorder Uniparental disomy Uniparental disomy ( UPD ) occurs when

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1890-440: The term exomphalos - macroglossia - gigantism (EMG) syndrome to describe the combination of congenital abdominal wall defects as hernia ( exomphalos ), large tongues ( macroglossia ), and large bodies and/or long limbs ( gigantism ). Over time, this constellation was renamed Beckwith–Wiedemann syndrome following the autoptical observations of Prof. John Bruce Beckwith (born 18 September 1933, Spokane, Washington), who also observed

1935-418: The two weeks after treatment. The trials only followed people for six months, so long-term outcomes are not known. Up to 10 treatments may be necessary for improvement, but complete removal may not result. The use of topical rapamycin as an adjunct to pulsed dye laser may improve results. Treatment is generally given before one year of age. With older laser treatments the skin is filled with black marks,

1980-425: The uncovering of recessive genes, a similar phenomenon seen in inbred children of consanguineous partners. UPD has been found to occur in about 1 in 2,000 births. UPD can occur as a random event during the formation of egg cells or sperm cells or may happen in early fetal development. It can also occur during trisomic rescue . Most occurrences of UPD result in no phenotypical anomalies. However, if

2025-515: 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, neonatal hypoglycemia). Another definition presented by Elliot et al. includes

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