Beckwith–Wiedemann and IMAGe syndromes: two very different diseases caused by mutations on the same gene

Abstract

Genomic imprinting is an epigenetically regulated mechanism leading to parental-origin allele-specific expression. Beckwith–Wiedemann syndrome (BWS) is an imprinting disease related to 11p15.5 genetic and epigenetic alterations, among them loss-of-function CDKN1C mutations. Intriguing is that CDKN1C gain-of-function variations were recently found in patients with IMAGe syndrome (intrauterine growth restriction, metaphyseal dysplasia, congenital adrenal hypoplasia, and genital anomalies). BWS and IMAGe share an imprinted mode of inheritance; familial analysis demonstrated the presence of the phenotype exclusively when the mutant CDKN1C allele is inherited from the mother. Interestingly, both IMAGe and BWS are characterized by growth disturbances, although with opposite clinical phenotypes; IMAGe patients display growth restriction whereas BWS patients display overgrowth. CDKN1C codifies for CDKN1C/KIP2, a nuclear protein and potent tight-binding inhibitor of several cyclin/Cdk complexes, playing a role in maintenance of the nonproliferative state of cells. The mirror phenotype of BWS and IMAGe can be, at least in part, explained by the effect of mutations on protein functions. All the IMAGe-associated mutations are clustered in the proliferating cell nuclear antigen-binding domain of CDKN1C and cause a dramatic increase in the stability of the protein, which probably results in a functional gain of growth inhibition properties. In contrast, BWS mutations are not clustered within a single domain, are loss-of-function, and promote cell proliferation. CDKN1C is an example of allelic heterogeneity associated with opposite syndromes.

Placental mesenchymal dysplasia: case report with gross and histological findings

“…Other instances were associated with androgenic/biparental mosaicism,4 and there were also cases that presented with aneuploidy. BWS has been related to imprinting alterations on 11p15.5, which may affect the expression of IGF-2, thus influencing growth of the fetus and placenta 11 , 14…”

“…BWS has been related to imprinting alterations on 11p15.5, which may affect the expression of IGF-2, thus influencing growth of the fetus and placenta. 11 , 14 …”

Mesenchymal Hamartoma of the Liver in an Infant With Beckwith-Wiedemann Syndrome: A Rare Condition Mimicking Hepatoblastoma

“…Early in the postnatal period, the patient manifested hemihypertrophy, omphalocele, a “dimple” on the right ear lobe, capillary hemangioma, and persistent hypoglycemia; methylation analysis confirmed BWS. 4 , 5 Serum α-fetoprotein (AFP) level was elevated at 814.3 ng/mL. Abdominal ultrasound (US) confirmed a large heterogeneous mass in the upper abdomen, displacing regional structures.…”

Sequence variants identification at the KCNQ1OT1:TSS differentially Methylated region in isolated omphalocele cases

“…Physiological expression of KCNQ1OT1 from the unmethylated paternal allele results in the bi-directional silencing of its flanking imprinted genes [ 13 ]. Among them, CDKN1C encodes P57 (alias KIP2 ), a tight-binding inhibitor of several G1 cyclin/Cdk complexes, acting as a negative regulator of cell proliferation [ 14 ]. The CDKN1C gene contains three exons and 2 GC-rich introns; however, only exons 1 and 2 encode the functional P57 protein.…”

“…Point mutations of CDKN1C are present in up to 5% of sporadic and 50% of familial cases of BWS [ 19 ]. Most frequently, CDKN1C mutations are truncating or frameshift and are distributed along the entire coding region; conversely, missense mutations are mainly localized in the CDK-like domain [ 14 ]. Almost 90% of BWS patients with CDKN1C mutations have abdominal wall defects [ 18 ]; in particular, omphalocele occurs in 71.6% of these cases [ 18 ].…”