Androgenetic chimerism as an etiology for Beckwith-Wiedemann syndrome: diagnosis and management

Abstract

Purpose: Beckwith-Wiedemann syndrome (BWS) is a human genomic imprinting disorder characterized by lateralized overgrowth, macroglossia, abdominal wall defects, congenital hyperinsulinism, and predisposition to embryonal tumors. One of the molecular etiologies underlying BWS is paternal uniparental isodisomy of chromosome 11p15.5 (pUPD11). About 8% of pUPD11 cases are due to genome-wide paternal uniparental isodisomy (GWpUPD). About 30 cases of live-born patients with GWpUPD have been described, most of whom were mosaic and female. We present male patients with BWS due to GWpUPD, elucidate the underlying mechanism, and make recommendations for management.

Methods: Three male patients with GWpUPD underwent clinical and molecular evaluation by single-nucleotide polymorphism (SNP) microarrays in different tissues. Previously published cases of GWpUPD were reviewed.

Results: SNP microarray demonstrated a GWpUPD cell population with sex chromosomes XX and biparental cell population with sex chromosomes XY, consistent with dispermic androgenetic chimerism.

Conclusion: SNP microarray is necessary to distinguish GWpUPD cases and the underlying mechanisms. The percentage of GWpUPD cell population within a specific tissue type correlated with the amount of tissue dysplasia. Males with BWS due to GWpUPD are important to distinguish from other molecular etiologies because the mechanism indicates risk for germ cell tumors and autosomal recessive diseases in addition to other BWS features.

Keywords: Beckwith–Wiedemann syndrome (BWS); chimera; genome-wide paternal uniparental isodisomy; mosaicism.

Fig. 1. Clinical and molecular features of patients.

a–c. Patient 1 at 4 weeks of age. Lateralized overgrowth (LO) of the (a) left cheek, (b) leg, and (c) foot with toes lengthening from great toe to fourth toe with space between fourth and fifth toe on larger left foot with bilateral feet with deep creases on plantar surface. Right foot measured 7 cm × 2.7 cm. Left foot measured 7.2 cm × 3.1 cm. d. Patient 1 at 9 months of age with esotropia, heterochromia, and LO of the left cheek. e Patient 3, critically ill with distended abdomen, diastasis recti, and right fifth toe hamartoma. f Patient 3, alive and well. g Patient 3, toe from multiple views. h Genome-wide view of single-nucleotide polymorphism (SNP) array B-allele frequency for patient 1 from blood. Genome-wide paternal uniparental isodisomy (GWpUPD) quantified to be 65%. i SNP array data viewed for part of chromosome 11 in order of highest percentage of GWpUPD to lowest: affected pancreas (80–85% GWpUPD), adrenal gland (65–60%), left leg skin (20%), and left side abdominal skin (5–10%). 11p15 is highlighted by the red box. j Percentage of GWpUPD by cell type in patients. ND not done.

Fig. 2. Hypothesized mechanisms for genome-wide paternal uniparental isodisomy (GWpUPD).

Legend: each bar represents a maternal or paternal haplotype. The X or the Y next to the bar indicates the associated sex chromosome. a Androgenetic chimera. Fertilization occurs between an egg with an anuclear polar body and two sperm. Haploidy rescue occurs leading to two cell line populations with three different haplotypes. b Androgenetic chimera. Fertilization occurs between an egg and two sperm. The second sperm pronucleus partially fails to fuse. Haploidy rescue occurs leading to two cell populations with three different haplotypes. c Androgenetic chimera. Fertilization occurs between an egg and two sperm to create a triploid embryo that undergoes diploidization. This is extremely unlikely as the main mechanism of triploidy is delayed incorporation. The zygote contains three haplotypes.