Beckwith–Wiedemann syndrome (BWS) is a rare syndrome and has anestimatedincidence of one in 13,700. It is also knownasexomphalos-macroglossia-gigantism syndrome. It consist of a combinationofcongenital abdominal wall defects such as hernias (exomphalos), largetongue(macroglossia), large bodies and/or long limbs (gigantism). There hasbeen anincrease observed in the number of cases of BWS in children born byassistedreproduction techniques (ART). Keywords: Beckwith-WiedemannSyndrome,assisted reproduction techniques. INTRODUCTION Beckwith-Wiedemannsyndrome (BWS) also known as EMG(Exomphalos, Macroglossia, Gigantism) syndromewas recognized independently byBeckwith in 1963 and Wiedemann in 1964. The incidence of BWS reported is 1 in 13700live births. This figure islikely an underestimate as milder phenotypes may notbe ascertained. Theincidence is equal in males and females with the notableexception ofmonozygotic twins that show a dramatic excess of females. The etiology is unknown but familial casessuggestive of autosomaldominance, autosomal recessive, polygenic inheritanceand delayed mutation havebeen recorded. There has been an increase observed inthe number of cases ofBWS or alterations in gene expressions in children bornby ART(assistedreproduction techniques ). A prenatal diagnosis of BWS is possible inpregnancy with uterine sizesincompatible with dates and by use of serialultrasound monitoring of theuterus of the pregnant woman.[3] Individuals withBWS may grow at an increased rate during the latterhalf of pregnancy and in thefirst few years of life. Growth parameterstypically show height and weightaround the 97th percentile with head sizecloser to the 50th percentile. Adultheights are generally in the normal range.
CASE REPORT A 36 weeks preterm male child(Fig.1) born to unrelated Indian parents by normal vaginal delivery was referred to our NICUfor omphalocele (Fig.2). The infant’s mother was a 32 year old second gravida. She had previously had a spontaneous abortion. This child was conceived with the help of assisted reproduction technique (ART). Her serial antenatal ultrasound scans had revealed an omphalocele with loops of bowel. The birth weight was 2200 gms,length was 52 cm and head circumference was 34cm.
Onexamination baby haddysmorphic features like bilateral nevus flammeus over eyelids (Fig.3),
macroglossia,omphalocele, hepatomegaly and undescended testes.The child was investigated for complete blood count and serum electrolytes which were within normal limits but the blood sugar level was low. The thyroid profile was normal. The baby was put on glucose infusion drip and also required steroids to remain euglycemic. Baby was operated successfully for the omphalocele on day5 of life. He later developed respiratory distress and a grade II/IV murmur was heard on auscultation. Echocardiography was suggestive of bilateral ventricular dilatation and a small sized ventricular defect. The child wasfurtherinvestigated for inborn errors of metabolism but no defect was detected.Abdominal ultrasonography showed a right adrenal cyst (Fig.4) and midjejunalatresia. Neuro sonography was suggestive of ischemia in the watershed areas of the brain. displayed areas of calcification. Chromosomalanalysisrevealed normal male karyo type. Baby developed respiratory distress on day 10 of life. He was put on assisted ventilation care but his condition kept deteriorating progressively. Baby died of respiratory failure on day 22nd of life. Autopsy finding showed evidence of intra-abdominal testis, kidney with increased foetal lobulations, disorganisation of the parenchyma, glomerularneogenesis and an increased number of immature collecting tubule. Pancreasrevealed an increased number ofacini, Adrenals showed cytomegaly and a right Adrenal cyst. DISCUSSIONBWS is a pediatric overgrowth disorder involving apredisposition to tumordevelopment. The characteristic features of BWS are variable, but mainly consist of macroglossia, fusion defects of the abdominal wall, somatic gigantism,midface hypoplasia, ear creases and/or pits, nevusflammeus, visceromegaly,cryptochidism and hemihypertrophy. The acronym EMGsyndrome was used earlier to describe exomphalos, macroglossia and gigantism.[4] Hypoglycemia is reported in 30–50% of babies with BWS, likely caused byislet cellhyperplasia and hyperinsulinemia. Abnormalities involving genes on chromosome 11that undergo genomicimprinting are responsible for most cases of BWS. Manypatients have abnormal DNA methylation in different areas of 11p15. Imprinting control regions (ICRS)control the methylation of several genes that are involved in normal growth,including the CDKN1C, H19, IGF2, and KCNQ1OT. Individuals with BWS may grow at an increased rate during the latter half of pregnancy andin the first few years of life, but adult heights are generally in the normal range. Abnormalgrowth may also manifest as hemihypertrophy and or macroglossia. There is an increased frequency of malformations and medical complications,including abdominal wall defects(omplalocele, umbilical hernia, and diastasisrecti) and visceromegaly involving liver, spleen, pancreas, kidneys or adrenals. Fetal adrenocorticalcytomegaly is a pathognomonic finding. Renal anomalies mayinclude primarymal formations, renal medullary dysplasia, nephrocacinosis, andnephrolithiasis. Most of the tumours associated with BWS occur in the first 8–10years of life with very few being reported beyond this age, most common areWilms tumor andhepatoblastoma. Other embryonal tumors include rhabdomyosarcoma,adrenocortical carcinoma, and neuroblastoma. Clinical findings associated with higher risks of tumour development include hemihyperplasia,nephromegaly, andnephrogenic rests. BWS has also been associated with congenital hypothyroidism inpreterm neonates in a few reports.It has been postulated that the gene governing the productionofthyroxin-binding globulin might be in close proximity with the one that governs the production of thyroxin and may well be linked closely to the gene that suppresses the manifestations of BWS.[4] However we did not find anysuchassociation. Differential diagnosis of BWS can be Sotos syndrome (Mutationsin the NSD1 gene on chromosome5q35), Silver-Russell syndrome (Hypo methylationdefects at 11p15), Fragile Xsyndrome, Berardinelli lip dystrophy syndrome,Marshall-smith syndrome,Weaver-smith syndrome. Diagnosis is based on clinical findings. The criteria for diagnosis isthe presence of 3 major findings(macroglossia, pre- or postnatal growth greater than the 90th centile, and abdominal walldefects) or 2 major findings plusminor manifestations. A careful cytogenetic analysis of the 11p15 region is recommended. Prenatal diagnosis by ultrasonography is also possible. When the pregnancy is not terminated, the prenatal diagnosis helps to prevent neonatal complications. The prenatal diagnosis helps because it allows two situations. On one hand, to prepare the parents,motivate them to have a periodic follow-up because of the increasing possibilities of developing tumors, and genetic counseling in case of the desire to have more children. The second situation is that it allows the planificationof the surgical interventions necessary for the correction of defects present in the child. The management of BWSpatients typically involves standard supportive medical and surgical strategies(e.g. surgical repair of omphalocele). In addition, anticipatory . medical management for certain findings should be invoked if thediagnosis of BWS is established or even suspected. If there are prenatal findings suggestive of or diagnostic for BWS screening for hypoglycemia should be undertaken in the first few days of life. As well, parents should be advised of the typical clinical manifestations of hypoglycemia in the event that it manifests after discharge from hospital. The management of BWS is according to the clinical features associated with it. The abdominal wall defects are treated by surgical repair.Hypoglycemia is treated as per standard protocols.Other features do not require any specific treatment. We have described an apparent increased frequency in children born with the aid of assisted reproductive technology (ART) in patients with the BWS imprinting disorder. As both IVF and ICSI procedures were associated with BWS, loss of maternal allelicmethylation at differentially methylated regions within imprinted gene clusters associated with in vitro embryo culture may be an important factor in the pathogenesis of ART associated imprinting disorders. CONCLUSION In children born with ART frequent antenatal ultrasound scan should be undertaken to establish the anticipatory medical management to prevent associated complications. Further studies are required to determine the precise relationship between human imprinting disorders and ART.