IllnessBeckwith-Wiedemann syndrome, differential diagnosis

1. methylation analysis
2. NGS + [Sanger] panel for DD, e.g. Costello, Malan, Perlman, PTEN-hanartoma, Simpson-Golabi-Behmel, Sotos, Weaver syndromes

Beckwith-Wiedemann syndrome (BWS) affects many parts of the body, e.g. with (asymmetric) macrosomia. Growth slows from about age 8, adults with BWS are not unusually tall. Also hemihyperplasias usually become less noticeable with time. Some children with BWS are born with an omphalocele or an umbilical hernia. Other symptoms include macroglossia, visceromegaly, folds or dimples in the skin near the ears, hypoglycemia in infancy and renal abnormalities. Children with BWS have an increased risk of developing Wilms tumor and hepatoblastoma occurring in about 10% of cases. However, most children and adults with BWS do not have serious medical problems, and their life expectancy is usually normal. The genetic causes of BWS are complex and are usually due to disturbed regulation of genes in a region of chromosome 11 due to impaired genomic imprinting, i.e. via methylation. At least half of BWS cases are due to alterations in differential methylation. Imprinting centers control the methylation of several genes involved in normal growth, including CDKN1C, H19, IGF2 and KCNQ1OT1. Approximately 20% of BWS cases are due to paternal uniparental disomy, in which there are two active copies of the paternally inherited genes, rather than one active copy from the father and one inactive copy from the mother. The genetic defect occurs early in embryonic development and results in somatic mosaicism. Less commonly, BWS is caused by mutations in the CDKN1C gene. About 1% of all people with BWS have a translocation, duplication, or deletion in chromosome 11. In about 85% of BWS cases, only one person in a family is diagnosed with the condition. Another 10-15% of people with BWS belong to families with more than one affected member. In most of these latter families, the disease appears to be inherited in an autosomal dominant manner, mostly from their mothers, occasionally with reduced penetrance. In rare cases, BWS results from changes in the structure of chromosome 11; some of these chromosomal abnormalities may be inherited. In up to 20% of BWS patients, the genetic defect can currently not be clarified. Thus the combined negative molecular genetic and cytogenetic results do not exclude the clinical diagnosis.

Reference: https://www.ncbi.nlm.nih.gov/books/NBK1394/

• Alias: BWS = Exomphalos-macroglossia-gigantism syndrome
• Alias: Beckwith-Wiedemann Spectrum
• Alias: Wiedemann-Beckwith syndrome
• Allelic: Leukemia, acute myeloid (NSD1)
• Beckwith-Wiedemann syndrome (IGF2)
• Beckwith-Wiedemann syndrome (NSD1)
• Beckwith-Wiedemann syndrome; IMAGE syndrome (CDKN1C)
• Chromosome 11p15.5-related Russell-Silver syndrome (IGF2)
• Costello syndrome; Schimmelpenning-Feuerstein-Mims s., somatic mosaic; Hemimegalencephaly (HRAS)
• Human overgrowth syndrome type (PIK3CA)
• Keipert syndrome (GPC4)
• Marshall-Smith syndrome; Sotos syndrome 2 (NFIX)
• Overgrowth with Intellectual disability (PTEN)
• Overgrowth with intellectual disability (PIK3CA)
• Perlman syndrome (DIS3L2)
• Silver-Russell syndrome 4 (PLAG1)
• Silver-Russell syndrome 5 (HMGA2)
• Simpson-Golabi-Behmel syndrome type 1 (GPC3)
• Sotos syndrome 1 (NSD1)
• Weaver syndrome; Weaver syndrome 2 (EZH2)