ESPE2022 Poster Category 2 Growth and Syndromes (44 abstracts)
Beckwith-Wiedemann Syndrome: Two Familial Cases with CDKN1C gene variants
Analía Freire 1 , Débora Braslavsky 1 , Paula Scaglia 1,2 , María Esnaola Azcoiti 1,2 , Romina Armando 2,3 , Anna Rothenfusser 1 , Bárbara Casali 1,2 , Claudia Arberas 2,3 , Rodolfo Rey 1,2 , María Gabriela Ropelato 1,2 & Ignacio Bergadá 1
1Centro de Investigaciones Endocrinológicas “Dr. César Bergadá” (CEDIE) CONICET – FEI – División de Endocrinología, Hospital de Niños Ricardo Gutiérrez., Buenos Aires, Argentina; 2Unidad de Medicina Traslacional. Hospital de Niños Ricardo Gutiérrez, Buenos Aires, Argentina; 3Sección Genética Médica. Hospital de Niños Ricardo Gutiérrez, Buenos Aires, Argentina
Introducción: Beckwith-Wiedemann syndrome (BWS) is a congenital disorder that includes features such as overgrowth, macroglossia, abdominal wall defects, neonatal hyperinsulinism, lateralized overgrowth and predisposition to embryonal tumors during infancy. BWS may be clinically diagnosed by a scoring system and genetic diagnosis is mainly focused to imprinting disorders on the 11p15.5 region. The presence of pathogenic inactivating variants on the maternal CDKN1C gene, although rare in sporadic cases, explains up to 50% of familial cases of BWS.
Objective: We describe two familial BWS cases and their genetic study.
Case 1: 8 year old boy, born preterm with macrosomia, macroglossia, nevus simplex, cryptorchidism and typical ear creases. BWS scoring=7.5 and negative screening for embryonal tumors. His mother was unaffected and two half-sisters had a clinical diagnosis of BWS, one with macrosomia, macroglossia, omphalocele at birth, and neuroblastoma at 3 months of life, the other with macrosomia and neonatal hypoglycemia.
Case 2: 18 month-old boy, born preterm with macroglossia, ear creases and aortic coarctation. BWS scoring=5. Macroglossia and omphalocele at birth was confirmed in the mother and five maternal family members.
Methods: Genomic DNA was isolated from peripheral blood and CDKN1C gene was studied by PCR amplification and Sanger sequencing variants were classified according to ACMG guidelines.
Results: Case 1: We found an already reported heterozygous pathogenic nonsense variant in exon1, NM_000076.2:c.388G>T, NP_000067.1:p.(Glu130Ter). The same loss of function variant was present in his unaffected mother (carrier), and his 2 half-sisters with BWS.
Case 2: Sanger sequencing revealed a novel heterozygous variant in exon 2, NM_000076.2:949T>C, NP_000067.1:p.(Ter317Argext*49). The same variant was found in his affected mother. According to ACMG classification criteria this is considered a variant of unknown significance (VUS). Segregation study in other affected and unaffected family members (in process) may add information for further classification of the variant as likely pathogenic.
Conclusion: Presumptive diagnosis of familial BWS orientated the molecular study strategy. Genetic confirmation allowed a supported genetic counseling including 50% recurrence risk in each pregnancy for both, BWS and unaffected, female variant carriers. Also, knowing the molecular mechanism underlying BWS allows individualized surveillance protocols.
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