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

Figures & data

Table 1 Molecular heterogeneity of BWS

Genetic mechanisms	Occurrence (%)	Methods of detection	Genotype/phenotype correlations
Paternal UPD	10–20	Microsatellite/SNP analysis, Southern blot, MS-MLPA, pyrosequencing, mass spectrometry	Hemihyperplasia, high risk of Wilms’ tumor and hepatoblastoma, severe phenotype (high level of somatic mosaicism UPD)
ID at ICR1 (gain of methylation)	2–8	Southern blot, MS-MLPA, pyrosequencing, mass spectrometry	Macrosomia, macroglossia, hemihyperplasia, high risk of Wilms’ tumor and hepatoblastoma
ID at ICR2 (loss of methylation)	50–60	Southern blot, MS-MLPA, pyrosequencing, mass spectrometry	Hemihyperplasia, omphalocele
Paternal 11p structural rearrangements	1–2	FISH, aCGH	Developmental delay
Mutations of the maternal CDKN1C allele	5–10 (sporadic cases) 40 (AD trait)	Sequencing	Cleft palate, omphalocele, genital anomalies, neuroblastoma

Notes: In column 4, the clinical features associated with the different genetic mechanisms are reported. The description is not exhaustive of the whole clinical presentation of BWS.

Abbreviations: BWS, Beckwith–Wiedemann syndrome; UPD, uniparental disomy; ICR, imprinting control region; ID, imprinting defects; AD, autosomal dominant; FISH, fluorescent in situ hybridization; aCGH, array comparative genomic hybridization; MS-MLPA, methylation specific-multiplex ligation-dependent probe amplification; SNP, single nucleotide polymorphism.

Figure 1 Mutations of CDKN1C in IMAGe syndrome (upper part) and BWS (lower part). The mutations in IMAGe syndrome are clustered within the PCNA-binding domain and are considered gain-of-function. The pathogenetic variations in BWS are spread throughout the gene and considered loss-of-function. The mutations reported here were previously described by Romanelli et al²⁹ and by Hamajima et al.⁴⁸

Abbreviations: BWS, Beckwith–Wiedemann syndrome; IMAGe, intrauterine growth restriction, metaphyseal dysplasia, congenital adrenal hypoplasia, and genital anomalies; PCNA, proliferating cell nuclear antigen.

Figure 2 Suggested follow-up for BWS according to risk classes.

Abbreviations: BWS, Beckwith–Wiedemann syndrome; pUPD, paternal uniparental disomy; ICR, imprinting control region; US, ultrasound.

Table 2 Mirror phenotypes in BWS and IMAGe syndrome

BWS	IMAGe syndrome
Macrosomia/hemihyperplasia	Short stature
Abdominal wall defects	–
Visceromegaly, macroglossia, increased risk of cancer	–
Adrenal hyperplasia	Adrenal hypoplasia
Anterior ear creases, posterior helical pits, cleft palate, nevus flammeus	–
Kidney abnormalities (cytomegaly of the adrenal fetal cortex, medullary dysplasia, delayed development of medullary sponge kidney), increased risk of cancer	Adrenal insufficiency
Neonatal hypoglycemia	–
Structural cardiac defects	–
Advanced bone age	Delayed endochondral ossification associated with osteopenia, hypercalcemia, and/or hypercalciuria
Fetal macrosomia (LGA), polyhydramnios, large/dysplastic placenta, long and thickened umbilical cord, increased risk for premature delivery	Intrauterine growth restriction
–	Metaphyseal dysplasia
–	Micropenis, undescended testes, and varying severity of hypospadias

Abbreviations: BWS, Beckwith–Wiedemann syndrome; IMAGe, intrauterine growth restriction, metaphyseal dysplasia, congenital adrenal hypoplasia, and genital anomalies; LGA, large for gestational age; SGA, small for gestational age.

RomanelliVBelinchónABenito-SanzSCDKN1C (p57(Kip2)) analysis in Beckwith–Wiedemann syndrome (BWS) patients: genotype-phenotype correlations, novel mutations, and polymorphismsAm J Med Genet A2010152A1390139720503313

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HamajimaNJohmuraYSuzukiSNakanishiMSaitohSIncreased protein stability of CDKN1C causes a gain-of-function phenotype in patients with IMAGe syndromePLoS One20138e7513724098681

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