• bladder or cloacal exstrophy
• ectopia cordis
• exomphalos
• myofibroblasts
• thoracoabdominoschisis
• ventral body wall development

• Animals
• Mice
• Humans
• Embryonic Development/physiology
• Morphogenesis/physiology
• Disease Models, Animal
• Embryo, Mammalian

• 095824/Z/11/Z Wellcome Trust
• 105082 University of Manchester
• PG/14/1/30549 British Heart Foundation
• Wellcome Trust
• BB/G021074/1/BB Biotechnology and Biological Sciences Research Council
• BB/W01730X/1 Biotechnology and Biological Sciences Research Council
• Biotechnology and Biological Sciences Research Council
• British Heart Foundation
• University of Manchester
• Wellcome Trust

• Congenital wall defects
• Neonatal surgery
• Omphalocele
• Paediatric surgery

• Humans
• Hernia, Umbilical/surgery
• Cross-Sectional Studies
• Retrospective Studies
• Female
• Male
• Esthetics
• Quality of Life
• Cicatrix/etiology
• Cicatrix/diagnosis
• Child
• Treatment Outcome
• Patient Satisfaction/statistics & numerical data
• Follow-Up Studies
• Infant, Newborn
• Adolescent
• Herniorrhaphy/methods
• Time Factors
• Child, Preschool

• Alma Mater Studiorum - Università di Bologna

• Imprinting disorders
• Isolated localized overgrowth
• MLPA
• Methylation

• F.8-642/A-642/2018/RS all india institute of medical sciences

• Beckwith–Wiedemann spectrum
• Beckwith–Wiedemann syndrome
• CDKN1C
• cancer predisposition
• overgrowth

• Humans
• Beckwith-Wiedemann Syndrome/genetics
• Beckwith-Wiedemann Syndrome/pathology
• Cyclin-Dependent Kinase Inhibitor p57/genetics
• Phenotype
• Male
• Female
• Neoplasms/genetics
• Neoplasms/epidemiology
• Neoplasms/pathology
• Genetic Predisposition to Disease
• Mutation/genetics
• Genetic Association Studies/methods
• Child, Preschool
• Genotype
• Child

• epigenetics and behaviour
• molecular neuroscience

• Humans
• Animals
• Mice
• Repressor Proteins
• GATA Transcription Factors/genetics
• Intellectual Disability/genetics
• Intellectual Disability/complications
• Transcription Factors/genetics
• Histone Deacetylases
• Syndrome
• Tumor Suppressor Proteins

• Helping Hands for GAND Foundation

• Beckwith-Wiedemann syndrome
• beta cell
• diabetes

• Humans
• Amino Acid Sequence
• Amino Acids/metabolism
• Cell Nucleus/metabolism
• Insulin-Secreting Cells/metabolism
• Nuclear Localization Signals/genetics
• Nuclear Localization Signals/metabolism
• Cyclin-Dependent Kinase Inhibitor p57/genetics

• P30 DK020541 NIDDK NIH HHS
• R01 DK105015 NIDDK NIH HHS
• R01 DK125285 NIDDK NIH HHS
• R01 DK129196 NIDDK NIH HHS
• Einstein-Sinai Diabetes Research Center
• Pilot and Feasibility Program
• NIH
• NIDDK

Cyclin-dependent kinase inhibitor 1C (CDKN1C) is a cell proliferation inhibitor that regulates the cell cycle and cell growth through G1 cell cycle arrest. CDKN1C mutations can lead to IMAGe syndrome (CDKN1C allele gain-of-function mutations lead to intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenital, and genitourinary malformations). We present a Silver-Russell syndrome (SRS) pedigree that was due to a missense mutation affecting the same amino acid position, 279, in the CDKN1C gene, resulting in the amino acid substitution p.Arg279His (c.836G>A). The affected family members had an SRS phenotype but did not have limb asymmetry or adrenal insufficiency. The amino acid changes in this specific region were located in a narrow functional region that contained mutations previously associated with IMAGe syndrome. In familial SRS patients, the PCNA region of CDKN1C should be analysed. Adrenal insufficiency should be excluded in all patients with functional CDKN1C variants.

We describe the case of an 8-year-old girl who initially presented with short stature. Her height was 91.6 cm, and her weight was 10.2 kg. Physical examination revealed that she had a relatively large head, an inverted triangular face, a protruding forehead, a low ear position, sunken eye sockets, and irregular cracked teeth but no limb asymmetry. Family history: The girl’s mother, great-grandmother, and grandmother’s brother also had a prominent forehead, triangular face, and severely proportional dwarfism but no limb asymmetry or adrenal insufficiency. Exome sequencing of the girl revealed a new heterozygous CDKN1C (NM_000076. 2) c.836G>A mutation, resulting in a variant with a predicted evolutionarily highly conserved arginine substituted by histidine (p.Arg279His). The same causative mutation was found in both the proband’s mother, great-grandmother, and grandmother’s brother, who had similar phenotypes. Thus far, we found an SRS pedigree, which was due to a missense mutation affecting the same amino acid position, 279, in the CDKN1C gene, resulting in the amino acid substitution p.Arg279His (c.836G>A). Although the SRS-related CDKN1C mutation is in the IMAGe-related mutation hotspot region [the proliferating cell nuclear antigen (PCNA) domain], no adrenal insufficiency was reported in this SRS pedigree. The reason may be that the location of the genomic mutation and the type of missense mutation determines the phenotype. The proband was treated with recombinant human growth hormone (rhGH). After 1 year of rhGH treatment, the height standard deviation score of the proband increased by 0.93 standard deviation score, and her growth rate was 8.1 cm/year. No adverse reactions, such as abnormal blood glucose, were found.

Functional mutations in CDKN1C can lead to familial SRS without limb asymmetry, and some patients may have glucose abnormalities. In familial SRS patients, the PCNA region of CDKN1C should be analysed. Adrenal insufficiency should be excluded in all patients with functional CDKN1C variants.

• CDKN1C
• Gene
• Silver-Russell syndrome
• Mutation
• Case report

• Beckwith-Wiedemann syndrome
• CDKN1C
• anticipation
• mosaicism

• Beckwith-Wiedemann
• CDKN1C
• imprinting disorders
• massive parallel sequencing
• methylation
• neoplasia
• overgrowth
• tumour

Beckwith–Wiedemann syndrome (BWS) is a complex imprinting disorder involving fetal overgrowth and placentomegaly, and is associated with a variety of genetic and epigenetic mutations affecting the expression of imprinted genes on human chromosome 11p15.5. Most BWS cases are linked to loss of methylation at the imprint control region 2 (ICR2) within this domain, which in mice regulates the silencing of several maternally expressed imprinted genes. Modelling this disorder in mice is confounded by the unique embryonic requirement for Ascl2, which is imprinted in mice but not in humans. To overcome this issue, we generated a novel model combining a truncation of distal chromosome 7 allele (DelTel7) with transgenic rescue of Ascl2 expression. This novel model recapitulated placentomegaly associated with BWS, but did not lead to fetal overgrowth.

Summary: A novel genetic mouse model of sporadic Beckwith–Wiedemann syndrome (BWS) recapitulates placentomegaly, but placental defects lead to late gestation fetal growth restriction, which contrasts with the fetal overgrowth characteristic of BWS in humans.

• Beckwith–Wiedemann syndrome
• Fetal growth restriction
• Mouse model
• Placentomegaly

• Beckwith-Wiedemann Syndrome/complications
• Beckwith-Wiedemann Syndrome/diagnosis
• Beckwith-Wiedemann Syndrome/genetics
• Beckwith-Wiedemann Syndrome/therapy
• Consensus
• DNA Copy Number Variations
• DNA Methylation
• Humans
• Molecular Diagnostic Techniques
• Neoplasms, Germ Cell and Embryonal/etiology
• Polymorphism, Single Nucleotide
• Prenatal Diagnosis
• Reproductive Techniques, Assisted

• Wellcome Trust
• K08 CA193915 NCI NIH HHS
• MR/J000329/1 Medical Research Council

Beckwith-Wiedemann syndrome (BWS) is a congenital overgrowth disorder mainly associated with altered genomic imprinting at chromosome 11p15.5. Children with BWS, especially uniparental disomy (UPD) at 11p15.5, are at increased risk of embryonal tumors including hepatoblastoma. Although genetic alterations of sporadic hepatoblastomas have been identified, integrated germline and somatic alterations of BWS-related hepatoblastoma have not been reported. For this, we performed whole-exome sequencing and genome-wide loss of heterozygosity/copy number analyses using a single nucleotide polymorphism (SNP) array for a hepatoblastoma in a BWS infant with paternal UPD at chromosome 11p15.5. We found germline 11p15.5 UPD as well as germline mutations of APC and PALB2 in the patient. At the somatic level, we found a CTNNB1 hotspot mutation and chromosome 1q gain in the tumor. The development of hepatoblastoma in this case might be explained by predisposition of the germline events (11p15.5 UPD, mutations of APC and PALB2) and later by somatic events with CTNNB1 somatic mutation and 1q gain. To our knowledge, this is the first report of germline and somatic genomic alteration profiles in hepatoblastoma arising from BWS. Clinically, our results provide a rationale for performing a more strict and intense protocol for hepatoblastoma surveillance in a high-risk BWS infant, such as the UPD-carrying case, for early detection and treatment.

• BWS
• copy number alteration
• hepatoblastoma
• mutation
• uniparental disomy

• CDK inhibitors
• cell cycle
• cell fate decision
• differentiation
• erythropoiesis
• hematopoiesis
• replication
• self renewal

• Animals
• Cyclin-Dependent Kinase Inhibitor p57/genetics
• Cyclin-Dependent Kinase Inhibitor p57/metabolism
• DNA Replication/physiology
• Erythroid Cells/cytology
• Erythroid Cells/metabolism
• Female
• Mice
• Mice, Mutant Strains
• S Phase/physiology
• Transcription, Genetic/physiology

• R01 GM098815 NIGMS NIH HHS
• R01 DK100915 NIDDK NIH HHS
• R01 CA095175 NCI NIH HHS
• R21 CA144017 NCI NIH HHS
• R01 DK099281 NIDDK NIH HHS
• Leukemia and Lymphoma Society
• National Institute of Diabetes and Digestive and Kidney Diseases
• National Cancer Institute
• National Institute of Health