Congenital hyperinsulinism in an infant with paternal uniparental disomy on chromosome 11p15: Few clinical features suggestive of Beckwith-Wiedemann syndrome

Abstract

Beckwith-Wiedemann syndrome (BWS) is the most common congenital overgrowth syndrome involving tumor predisposition. BWS is caused by various epigenetic or genetic alterations that disrupt the imprinted genes on chromosome 11p15.5 and the clinical findings of BWS are highly variable. Hyperinsulinemic hypoglycemia is reported in about half of all babies with BWS. We identified an infant with diazoxide-unresponsive congenital hyperinsulinism (HI) without any apparent clinical features suggestive of BWS, but diagnosed BWS by molecular testing. The patient developed severe hyperinsulinemic hypoglycemia within a few hours after birth, with macrosomia and mild hydronephrosis. We excluded mutations in the K(ATP) channel genes on chromosome 11p15.1, but found a rare homozygous single nucleotide polymorphism (SNP) of ABCC8. Parental SNP pattern suggested paternal uniparetal disomy in this region. By microsatellite marker analysis on chromosome 11p15, we could diagnose BWS due to the mosaic of paternal uniparental disomy. Our case suggests that some HI of unknown genetic etiology could involve undiagnosed BWS with no apparent clinical features, which might be diagnosed only by molecular testing.

Congenital Hyperinsulinism and Cochlear Hypoplasia in a Rare Case of Pallister-Hall Syndrome

“…Our patient also had CHI, which has been described in the literature in association with various syndromes (Table 2) [3] such as Beckweth-Wiedemann syndrome [16], Soto's syndrome [17], Usher's syndrome [18], and Costello syndromes [3]. However, the association of CHI in PHS has not been previously reported in the literature.…”

Severe Hyperinsulinaemic Hypoglycaemia in Beckwith-Wiedemann Syndrome due to Paternal Uniparental Disomy of 11p15.5 Managed with Sirolimus Therapy

“…HH can be a feature of BWS in about half of these individuals [1,8]. Loss of methylation in KvDMR1 occurs in approximately 50% of BWS patients, and 20% of patients with BWS have paternal UPD of chromosome 11p15 [2,8]. Those patients with paternal UPD of chromosome 11p15.5 usually require a near-total pancreatectomy to alleviate hypoglycaemia.…”

“…Clinically, BWS presents with overgrowth, macroglossia, organomegaly, hemihypertrophy, midline abdominal wall defects, ear lobe creases, renal abnormalities and in some cases hyperinsulinaemic hypoglycaemia (HH) [1]. Genetically, BWS is caused by genetic and epigenetic alterations affecting the imprinted growth-regulatory genes located on chromosome 11p15 [2]. Approximately 50% of all cases result from methylation alterations in imprinting control regions 1 and 2 (known as KvDMR1, a locus that regulates expression of multiple genes) in chromosome 11, which lead to impaired imprinting of genes IGF2, H19, CDKN1C and KCNQ1OT1 .…”

“…About 20% of BWS cases are found to have mosaic paternal uniparental disomy (UPD) of chromosome 11p15, hence they have increased expression of the paternally expressed growth promoter IGF2 and reduced expression of the maternally expressed CDKN1C and H19 genes. In about 5% of patients, BWS can be caused by mutations in the CDKN1C gene, and even less common (1-2%) are chromosomal abnormalities such as translocation or duplication of the genetic material from chromosome 11p15.5 [2]. …”

Coexistence of Mosaic Uniparental Isodisomy and a KCNJ11 Mutation Presenting as Diffuse Congenital Hyperinsulinism and Hemihypertrophy

“…The report by Kocaay et al [2] and 2 previous reports [3,4] highlight several important aspects of patients with BWS and HH due to paternal UPD of chromosome 11. Patients with BWS and HH may not always have the classical features of macrosomia, macroglossia, hemihypertrophy, and abdominal wall defects at birth.…”