Handbook of Genetic Counseling/Beckwith-Wiedemann Syndrome

Beckwith-Wiedemann Syndrome Overview Disorder of growth characterized by macrosomia (large body size), macroglossia (large tongue), visceromegaly(large organs), omphalocele, neonatal hypoglycemia, ear creases/pits embryonal tumors (i.e., Wilms tumor (kidney tumor), hepatoblastoma (liver tumor), and less commonly neuroblastoma, rhabdomyosarcoma). Genetic Etiology Mode of inheritance: Usually sporadic ~85% have negative family history 15% have history consistent with AD inheritance with incomplete penetrance and preferential maternal transmission Believed to be a multigenic disorder caused by alterations in growth regulatory genes on chromosome 11p15 Molecular genetics: 10-20% of patients have parental uniparental disomy (UPD), with two paternal copies of 11p15. Patients with UPD show somatic mosaicism, so the incidence of UPD is probably underestimated. UPD or mutation in gene found in 15-30%. <1% have a chromosome abnormality involving 11p15 Incidence Incidence is 1 in 13,700, with equal occurrence in males and females Probably underestimate given potential mild undiagnosed cases Diagnosis Primarily clinical No consensus diagnostic criteria Dx. generally accepted if have 3 findings (2 major 1 minor) Major Findings Positive family history (one or more family members with a clinical diagnosis of BWS or a history or features suggestive of BWS) Macrosomia (traditionally defined as height and weight >97th %) Anterior linear ear lobe creases/posterior helical ear pits Macroglossia Omphalocele (also called exomphalos), umbilical hernia Visceromegaly involving one or more intra-abdominal organs including liver, spleen, kidneys, adrenal glands, and pancreas Embryonal tumor (e.g., Wilms tumor, hepatoblastoma, rhabdomyosarcoma) in childhood Hemihyperplasia defined as asymmetric overgrowth of region(s) of the body Adrenocortical cytomegaly Renal abnormalities including structural abnormalities, nephromegaly, nephrocalcinosis Cleft palate (rare) Minor Findings Polyhydramnios Prematurity Neonatal hypoglycemia Facial nevus flammeus (stork bite) Hemangioma Characteristic facies, including midfacial hypoplasia and infraorbital creases Cardiomegaly/structural cardiac anomalies/rarely cardiomyopathy Diastasis recti - Advanced bone age Monozygotic twinning. Monozygous twins with BWS are usually female and discordant; however, both male and female monozygous twins concordant for BWS have been reported, as well as monozygous male twins discordant for BWS Individuals presenting with fewer than three features, e.g., macroglossia and umbilical hernia or just hemihyperplasia, should be considered candidates for tumor surveillance Testing High resolution chromosomes are recommended Molecular testing for those with normal karyotype can sometimes confirm dx. and better define recurrence risks (UPD) by restriction fragment length polymorphism (RFLP) analysis of genes in the 11p15 region screening for p57 KIP2 mutations available only on a research basis by heteroduplex/SSCP analysis if positive gene is sequenced then confirmation of positive results in a clinical laboratory prenatal testing available ultrasound can sometimes detect macroglossia, increased growth for gestational age, omphalocele, minor signs such as polyhydramnios, large placenta genetic testing with amnio or CVS if mutation known or for UPD (although detection rate poor using UPD testing) Clinical Features (numbers vary) Prenatal findings: polyhydramnios, premature birth, fetal macrosomia, enlarged placenta, long umbilical cord 20% infant mortality rate (mostly complications of prematurity, omphalocele, macroglossia, neonatal hypoglycemia (cardiomyopathy rare) Neonatal hypoglycemia (30-50% of babies) usually mild and transient Hypothyroidism, hyperlipidemia/hypercholesterolemia and polycythemia less common Macrosomia (height and weight >97th percentile) (87%) usually present at birth but can occur postnatally Most have rapid growth in early childhood but eventual height usually in upper range of normal Anterior linear ear lobe creases and/or posterior helical ear pits Macroglossia (usually at birth but may occur postnatal) Abdominal wall defects common (omphalocele, umbilical hernia, diastasis recti) Visceromegaly involving one or more intra-abdominal organs including liver, spleen, kidneys, adrenal glands, and pancreas Tumors both malignant and benign -- Wilms tumor, hepatoblastoma, (most common) Overall incidence of tumors is 7.5% (5-10%), but uncommon after 8 years old Hemihyperplasia (25%) usually noticed at birth, but may be more evident w/ growth (segmental or selected organs) Adrenocortical cytomegaly Renal abnormalities (structural abnormalities, nephromegaly, nephrocalcinosis, cystic changes) Cardiomegaly (between 4-17% of patients) Advanced bone age Midfacial hypoplasia and infraorbital creases Development Usually normal unless chromosome abnormality or birth complication Mental retardation/developmental delay (if a chromosome abnormality is found) Age of Onset, Natural History, and Life Span Age of onset is birth. There is a good prognosis for long-term health and development, but 20% will die in the perinatal period of complications. Natural History: Macroglossia and macrosomia are usually present at birth, although postnatal onset can occur. Neonatal hypoglycemia is common. Hemihyperplasia becomes more apparent as the child grows and may be limited to only one side of the body. Although cardiomegaly is common, it usually resolves on its own. Childhood malignancies and renal anomalies pose large health threats and mortality risks. After childhood, the complications for patients with BWS are infrequent. Surveillance, Management, and Treatment Options Newborns should be screened for hypoglycemia within the first seven days of life. Early treatment of hypoglycemia minimizes CNS complications. Patients with abdominal wall defects may undergo surgical repair Jaw grows and tongue growth usually slows down but… Severe macroglossia may benefit from surgery (between two and four years of age). If macroglossia should be followed by a craniofacial team If hemihyperplasia significant should be followed by an orthopedist. Order renal ultrasound If renal anomalies refer to nephrologist Once a patient is eight years, may be monitored with an annual renal ultrasound until adolescence Patients should also have an abdominal ultrasound every three months until eight years of age to screen for embryonal tumors. Baseline MRI and CT examination of abdomen is also recommended Serum AFP part of screening protocol for first few years of life (screen for hepatoblastoma and risk for it drops off significantly after 3 years) Periodic chest x-ray and urinary VMA and VHA assays to screen for neuroblastoma have been suggested, but have not been incorporated into most screening protocols because of their low yield and fortunately they are rare Comprehensive cardiac eval prior to any surgery or if cardiac problem suspected Recurrence Risks Unknown if no identifiable etiology, but probably low Very low if paternal UPD of 11p15 is present (normal karyotype and neg. fam hx) Up to 50% if p57 KIP2 mutation present in parent Positive family history normal karyotype up to 50% Cyptogenetically detected maternal translocation or inversion may be up to 50% with preferential maternal transmission Risk to Sibs of a Patient with BWS Based on Family History and Genetic Characteristics % of Patients with BWS Characteristics Risk to Sibs of Patient with BWS Prenatal Test Availability / Test Type ~85% Negative family history, normal karyotype 1, 2 Unknown but probably low if no identifiable molecular etiology No Very low if paternal UPD of 11p15 is present Up to 50% if p57 KIP2 mutation is present in a parent Yes, if p57 KIP2 mutation analysis confirmed by clinical laboratory ~10-15% Positive family history, normal karyotype 2 Up to 50% Yes, only if p57 KIP2 mutation analysis documented in a clinical laboratory or linkage analysis is available (see above caveats) <1% Cytogenetically detected maternal 11p15 translocation or inversion May be as high as 50% with preferential maternal transmission Yes / karyotype <1% Cytogenetically detected paternal 11p15 duplication Not defined <1% Monozygous twins Low No 10-20% of patients with sporadically occurring BWS have paternal uniparental disomy of 11p15 5-10% of all patients with BWS with a normal karyotype have identifiable mutations in p57 KIP2 table taken from geneclinics/genetests Differential Diagnoses Simpson-Golabi-Behmel syndrome: patients have macrosomia, visceromegaly, macroglossia, and renal cysts, but also exhibit coarse features, cleft lip, a high incidence of cardiac abnormalities, supernumerary nipples, polydactyly, and skeletal anomalies. Perlman syndrome: patients have macrosomia, MR, and renal tumors, but also have a characteristic facial appearance different from that of BWS. Costello syndrome: this syndrome resembles BWS only in the neonatal period, since both are overgrowth syndromes. Children with Costello syndrome have very coarse facial features and failure to thrive. Isolated hemihyperplasia - increase for tumors (5.9%) and offered tumor surveillance Or hemihyperplasia associated with other syndromes (proteus, klippel-Trenauny-Weber, NF1) Notes The information in this outline was last updated in January 2003.